Downs syndrome is a chromosomal abnormality and it is the number one cause of mental deficit of genetic origin. Its screening and management have evolved a lot. What tests are currently carried out on pregnant women? When is an amniocentesis done? Causes, examinations, symptoms, treatment…
This is a special case of aneuploidy. Normally, chromosomes go in pairs (23 pairs in humans). In the case of a trisomy, at least one of the pairs is a triplet, hence the name “trisomy”.
This can occur if either parent brings two chromosomes instead of one; this phenomenon can also occur by poor distribution during the first cell division, which is the most frequent case, or during the second or subsequent cell division. The cells of the individual will in this case be a mixture of healthy cells and cells with Down’s syndrome. We speak in this case of mosaic trisomy. If, on the contrary, all the cells are affected, we speak of homogeneous trisomy.
Trisomy is said to be free if the chromosomes are detached from each other; in the event of translocation, the extra chromosome is attached to another.
The term “Down’s syndrome” is generally used to refer to a person with trisomy 21, or Down syndrome, but trisomies can involve any pair of chromosomes. Depending on the chromosome concerned, and the type of trisomy (mosaic or not), the affected individual will be viable or not.
In humans, most trisomies lead to natural abortion (miscarriage), but some result in the birth of children alive.
Trisomy 21 – sometimes called Down Syndrome – was discovered in 1959 by a group of French doctors: Marthe Gautier, Jérôme Lejeune, and Raymond Turpin. The term “trisomy” emphasizes a genetic disorder with 3 chromosomes – tri – instead of two on chromosome 21, hence the term trisomy 21.
The cause of Down’s syndrome is not known. It is the result of an accident that occurred during the separation of the chromosome.
In the majority of cases, 95%, it is a free trisomy linked to the non-separation of chromosome 21;
In 2-3%, it is said to be mosaic;
and in the remaining 2-3% is the so-called translocation trisomy when the extra chromosome 21 is integrated with another chromosome.
Today, pregnancy at a late age is the only accepted risk factor for Down’s syndrome. Indeed, the risk increases with the mother’s age. At 38, the risk becomes greater than 1/250 then 1/100 at 40 years.
Trisomy 21 is characterized by the following symptoms:
- mental retardation
- a round face
- a small nose
- more or less significant cognitive disorders
- a single palmar fold
- slanting eyes
- a flattened neck
- broad hands and short fingers
- hypotonia (a lack of muscle tone)
- one size smaller
- slower growth
There is no way to prevent the onset of Down’s syndrome.
Combined screening for trisomy 21 in the first trimester of pregnancy is offered to all pregnant women. It associates with the first trimester of pregnancy:
ultrasound measurement of the clarity of the fetal neck;
the assay of maternal serum markers.
The obstetrician gynecologist, sonographer and biologist are in contact for these screenings.
In the event of abnormal results of these examinations, the risk of Down’s syndrome is assessed. If this risk is high (greater than or equal to 1/250), an amniocentesis is performed. It consists in taking amniotic fluid which makes it possible to determine the karyotype of the fetus and therefore to affirm or eliminate, with certainty the existence of a trisomy 21. The practice of amniocentesis is limited because it is an examination. invasive, with risk of infection and miscarriage.
Evolving screening methods
New genetic screening tests look for, from a blood sample taken from the mother, an overrepresentation of fetal DNA from chromosome 21 in free fetal DNA circulating in the maternal blood. Since January 2019, these tests have been covered by Social Security:
the free circulating DNA test for T21 is offered, after a combined 1st trimester screening, to women whose estimated risk level is between 1 in 1000 and 1 in 51;
for women whose risk is greater than or equal to 1 in 50, the recommendation is to perform an amnocientesis.
Amniocentesis would still be necessary to definitively confirm the diagnosis, but this invasive examination would be offered to fewer women (the number of fetal karyotypes would be divided by four), even though the detection rate for trisomy 21 would increase by around 15 % thanks to the performance of genetic tests.
The three types of Down’s syndrome
Research has determined that this chromosomal abnormality, which is the result of a nondisjunction, can present in three different forms which give rise to three types of Down’s syndrome, namely free trisomy, mosaic trisomy and trisomy. by translocation.
Free trisomy or complete and homogeneous trisomy 21
Free trisomy affects about 95% of people with trisomy 21. It is the result of an error in the distribution of chromosomes, which occurs during the first cell division. It affects all cells in the human body.
Mosaic trisomy occurs during the second cell division and affects about 2% of the population of people with trisomy 21. In this case, there is a combination of cells that have 46 chromosomes and cells that have 47 chromosomes.
People with mosaic trisomy sometimes present differences compared to other people with free trisomy: less obvious physical features, more cognitive potential, etc. However, it should be avoided to conclude that these people will be less affected by trisomy, because it is not possible to know which cells have a third chromosome.
Trisomy by translocation
In this type, there are about 3% of people with Down’s syndrome.
Translocation trisomy means that part of chromosome 21 has been broken. In this case, the child receives this translocated chromosome in his genetic makeup from one of the parents, who is himself a carrier, although that he is not affected by the syndrome.
A meeting with a geneticist will verify the risks of giving birth to another child with Down’s syndrome.
No treatment per se can improve the intellectual capacities of people with Down’s syndrome. On the other hand, the quality of medical follow-up and the quality of education are essential factors in the development and autonomy of people with Down’s syndrome.
Good medical follow-up from childhood is important. “Medical monitoring by qualified health professionals is therefore recommended throughout life” can be read on the website of the Association Perce-Neige, which takes care of disabled people. An early follow-up is set up by a multidisciplinary team with a physiotherapist, a speech therapist. Children with Down’s syndrome are often in special schools, although there are also successful examples of children with Down’s syndrome who attend mainstream schools. Today, many people with Down’s syndrome are employed, often after manual training.
The median life expectancy is over 50 years, but advances in medicine are increasing that life expectancy.
In addition to impaired cognitive development, people with Down’s syndrome often have a diverse set of birth defects such as heart disease. However, life expectancy – and healthy life – has improved a lot since heart and lung problems were first brought under control from childhood. There are also musculoskeletal abnormalities in people with Down’s syndrome which can cause certain problems.
Almost 30% of the population with Down’s syndrome have one of the following abnormalities: dislocations, acetabular dysplasia, joint hyperlaxity, muscle hypotonia, joint instability, lack of control over voluntary movements and static and dynamic balance. Thanks to advances in medicine, a better lifestyle and preventive care, we are now witnessing more and more children with Down’s syndrome changing to adolescent and adult status.
Consequently, the problems associated with aging affecting T21 customers have become, over the years, a major issue for the organization.
Intellectual disability and development
The developmental effects of Down’s syndrome vary from person to person. Although the impairment can sometimes be severe, people with carriers have an intellectual disability that generally ranges from mild to moderate (WHO describes an IQ between 50 and 69 as mild retardation). Therefore, with the right stimulation and resources, most of these people are able to integrate into society on their own as adults.
Experience has shown that it is possible to intervene at an early age through early stimulation and thus help with motor development, intellectual development and language development. Stimulating the development of a child with Down’s syndrome is not that much different from stimulating any other child. It’s about :
to encourage him to have confidence in himself;
to encourage him to make plans;
support the development of social skills;
support the development of social skills;
to recognize his strengths and make him proud of his achievements;
to name its progress;
listen to his point of view.
In addition to parental involvement, expert advice will help support the development of children with Down’s syndrome, so that they can thrive and thrive like any other child.
As for the education of children with Down’s syndrome, whether the choice is traditional schools or specially supervised classes, it is not only possible, but essential. With the right materials and the support of parents, teachers and the entire educational community, learning to read and write can also be accessible to them, depending on their personal potential.
An increased risk of certain diseases
People with Down’s syndrome are more susceptible to infections. They suffer more frequently from heart, organ, digestive or abdominal malformations. They are also more vulnerable to ENT problems, epilepsy or certain autoimmune diseases.
They may also be more exposed to pathologies such as diabetes, hyper or hypothyroidism.
One of the key elements in monitoring people with Down’s syndrome is visual impairment. Thus, in the general population, cases of cataracts occur around age 70, while in people with Down’s syndrome, it can happen from age 40.
Beyond strictly medical care, psychological support may be recommended. It is important, for the well-being of the person with Down syndrome and that of those around him, not to be isolated.
Down syndrome can affect any chromosome; but the size of the supernumerary chromosome being a risk factor for miscarriage, we therefore mainly encounter trisomies 21 which is the smallest human chromosome1. Trisomies 13 and 18 can also result in the full term birth of a live child, but the child will most often die within a few weeks2. The rest of the cases are viable only with mosaic trisomy.
- chromosome 1: mosaic trisomy 1 is an extremely rare form
- chromosome 2: mosaic trisomy 2 is a rare form with a highly variable phenotype4
- chromosome 3: mosaic trisomy 3 is a rare form
- chromosome 4: mosaic trisomy 4 causes growth retardation, mild intellectual deficit, heart abnormalities, facial dysmorphia, thumb malformation and skin abnormalities
- chromosome 5: mosaic trisomy 5 can be asymptomatic or cause various birth defects
- chromosome 6: mosaic trisomy 6 is one of the rarest forms (7 known cases)
- chromosome 7: mosaic trisomy 7 is a rare form with a highly variable phenotype
- chromosome 8: trisomy 8 causes Warkany syndrome
- chromosome 9: trisomy 9 is extremely rare, a few cases of complete trisomy have been described10
- chromosome 10: Mosaic trisomy 10 is usually fatal in infancy
- chromosome 11: mosaic trisomy 11 has only been documented in 3 cases
- chromosome 12: Mosaic trisomy 12 is a rare form that can cause various abnormalities
- chromosome 13: trisomy 13 causes Patau syndrome
- chromosome 14: mosaic trisomy 14 is a rare form with a highly variable phenotype
- chromosome 15: mosaic trisomy 15 causes intrauterine growth retardation and cardiac and craniofacial abnormalities
- chromosome 16: mosaic trisomy 16 is a rare form with a variable phenotype
- chromosome 17: mosaic trisomy 17 is a rare form, its clinical presentation is highly variable
- chromosome 18: trisomy 18 causes Edwards syndrome
- chromosome 19: mosaic trisomy 19 is only known in 4 cases
- chromosome 20: mosaic trisomy 20 is a rare form that is usually asymptomatic
- chromosome 21: trisomy 21 causes Down syndrome
- chromosome 22: mosaic trisomy 22 is a rare form that can cause various manifestations
The chromosomal formula of homogeneous trisomies of autosomes is of the form 47, Xa, + b with:
a: X for girls and Y for boys
b: the number of the excess chromosome
For example 47, XY, + 21 for trisomy 21 in a boy21. For mosaic trisomies a slash is added followed by the normal chromosomal formula, a mosaic trisomy 10 will thus be designated by 47, XX, + 10/46, XX.
Trisomies usually result from nondisjunction. Non-disjunction can occur during maternal or paternal gametogenesis (in humans it is overwhelmingly of maternal origin). This is a cell division error in which there is a failure of a chromosome pair to come apart. This results in an uneven distribution of a pair of chromosomes homologous to the daughter cells: the whole chromosome pair passes to one of the daughter cells and the other daughter cell receives nothing.
Upon fertilization, the cell with one chromosome pair receives a third chromosome from the other gamete, thus becoming a zygote with Down’s syndrome (when the other daughter cell is fertilized, this causes a monosomy).
When nondisjunction occurs after fertilization, a mosaic trisomy is obtained.
Sometimes the Down’s syndrome zygote heals itself by losing one of the three extra chromosomes (trisomy reduction), which can cause uniparental disomy when the two chromosomes retained come from the same parent.
Down’s syndrome affects a large number of pregnancies, the risk increasing with the age of the mother: from about 2% of pregnancies at 25 years, up to 35% at 40 years; most of these pregnancies will end in miscarriage. Trisomy 16 is the most frequently encountered, it is estimated that it affects 1 to 1.5% of pregnancies. Trisomies 15 and 22 are the two other common forms, they also cause the death in utero of the affected fetus. It is possible that these results are biased by the failure to detect very early pregnancy failure for certain trisomies; in fact, the relative frequency of trisomies detected by preimplantation diagnosis is more homogeneous.
Among viable pregnancies; the most frequent trisomy is trisomy 21 or Down syndrome, estimated at 1/800 births without prenatal diagnosis. The other trisomies of the autosomes are rarer: 1/8000 births for trisomy 18; 1 / 100,000 for trisomy 13. However, most pregnancies fail spontaneously: in 75% of cases for trisomy 21 30 and more than 95% for trisomies 18 and 1331.
Duplications of sex chromosomes are quite common. Trisomy X affects 1/1000 of births to girls; XXY syndrome 1/500 of boy births and 1/1000 for the XYY34 form.
Children with Down’s syndrome 13 and 18 generally only live from a few days to a few weeks because of the importance of the associated malformations.
Down’s syndrome disrupts brain development, causing cognitive deficits and impaired behavior. However, by dint of stimulation, people with Down’s syndrome can develop intellectually and emotionally as well as professionally, even if their disability will never allow them to reach the mental age of an adult.
Syndromes caused by a trisomy of the sex chromosomes are less severe and are often even asymptomatic. They are mainly manifested by problems with sexual development or fertility. The protective mechanisms are probably linked to the inactivation of the X chromosome and the low number of genes carried by the Y2 chromosome.
Edwards syndrome, also called trisomy 18
Edwards syndrome, also called trisomy 18, is a congenital chromosomal disease caused by the presence of an extra chromosome for the 18th pair. This malformation syndrome usually leads to early death. This disease was described by the English geneticist John H. Edwards in a 1960 article.
Most cases of trisomy 18 result from the presence of three copies of chromosome 18 in each cell of the body instead of the usual two copies. The extra genetic material disrupts the normal course of development, causing the characteristic traits of Down’s syndrome.
About 5 percent of people with Down’s syndrome have an extra copy of chromosome 18 in only certain cells in the body. In these people, the condition is called mosaic trisomy 18. The severity of mosaic trisomy 18 depends on the type and number of cells that have the extra chromosome. The development of individuals with this form of trisomy 18 can range from normal to severely affected.
Very rarely, part of the long arm (q) of chromosome 18 attaches to another chromosome during the formation of reproductive cells (eggs and sperm) or very early in embryonic development. Affected individuals have two copies of chromosome 18, plus extra material from chromosome 18 attached to another chromosome. People with this genetic change would have partial trisomy 18. If only part of the arm q is present in triplicate, the physical signs of partial trisomy 18 may be less severe than those typically seen in trisomy 18. If the all of the q arm is present in triplicate, individuals can be as severely affected as if they had three complete copies of chromosome 18.
Most cases of trisomy 18 are not hereditary, but occur as random events during the formation of eggs and sperm. An error in cell division called nondisjunction results in a reproductive cell with an abnormal number of chromosomes. For example, an egg or a sperm cell can gain an extra copy of chromosome 18. If one of these atypical reproductive cells contributes to a child’s genetic makeup, the child will have an extra chromosome 18 in every cell in the body. .
Mosaic trisomy 18 is also not inherited. It occurs as a random event during cell division at the start of embryonic development. As a result, some cells in the body have the usual two copies of chromosome 18, and other cells have three copies of this chromosome.
Partial trisomy 18 can be inherited. An unaffected person can rearrange genetic material between chromosome 18 and another chromosome. This rearrangement is called a balanced translocation because there is no additional material from chromosome 18. Although they do not show signs of trisomy 18, people who carry this type of balanced translocation are at increased risk of. have children with the disease.
People with trisomy 18 often have slow growth before birth (intrauterine growth retardation) and low birth weight. Affected people may have heart defects and abnormalities of other organs that develop before birth. Other features of Down’s syndrome include a small, abnormally shaped head; a small jaw and a mouth; and fists clenched with overlapping fingers. Due to the presence of several life-threatening medical conditions, many people with Down’s syndrome die before birth or during their first month. Five to 10 percent of children with this disease live past their first year, and these children often suffer from severe intellectual disability.
Children with the condition usually only survive a few weeks and not longer than a year. There are a few reported cases of patients who have survived at least to the age of 19. Despite everything, it is rarer than trisomy 21, which is the most common and the most viable of the trisomies. However, it is like trisomy 13 much more serious than trisomy 21 because the majority of cases die in utero before 6 months, because this trisomy 18 prevents the development of the newborn.
This is a rare chromosomal abnormality affecting approximately one in 6,000 people2.3.
Dolichocephaly (protruding occiput and short TID)
Small mouth, micrognathia
Fauna ears: pavilions not very hemmed, flat, pointed in their upper part.
Tightness of the pelvis
Characteristic hands: closed fists, index finger covers the middle finger, the little finger covers the ring finger.
Attitude of the supplicant – ice ax.
Cardiac: CIV (Interventricular communication), CA, CIA …
Pulmonary, gastrointestinal, renal…
Trisomy 13, or Patau’s syndrome
Trisomy 13, or Patau’s syndrome, is the condition that results from the presence of an extra 13 chromosome. The chromosome formula of patients is therefore 47 chromosomes instead of the 46 chromosomes in humans. Klaus Patau was the first to describe trisomy 132 in 1960.
While trisomy 13 is the rarest of the trisomies that can lead to a full term birth of a living child3, it is also the most frequent chromosomal abnormality characterized by multiple malformations and which leaves little hope of survival. after diagnosis 1. This pathology affects a large number of organs. It was in 1960 that Patau discovered the extra chromosome. Survival until adulthood is possible, especially in cases of mosaicism.
The fetuses have intrauterine growth retardation with at least some of the following symptoms:
Nervous system abnormalities
Holoproencephaly is the most common malformation (50%)
Ventricular junction dilation
Enlargement of the posterior fossa
Decrease in inter-orbital distance (hypotelorism) up to the presence of only one eye achieving the cyclops aspect
Increased kidney size
Tetralogy of Fallot
The karyotype by amniocentesis, fetal blood sample or trophoblast biopsy makes the diagnosis.
It is essential to make an exact diagnosis for the most precise genetic counseling possible in parents.
This chromosomal disease should be differentiated from the following genetic abnormalities:
- Cohen-Gorlin syndrome (a rare disorder of embryonic development characterized by microcephaly, facial dysmorphia, hypotonia, non-progressive intellectual disability, myopia, retinal dystrophy, neutropenia, and body obesity).
- Meckel-Gruber syndrome (a rare poly-malformation syndrome, autosomal recessive transmission, defined by occipital encephalocele, polydactyly, and renal cystic dysplasia. Ultrasound is currently the best way to antenatal screening for this lethal polyformation and its confirmation is done by studying the karyotype. We reported a case of Meckel’s syndrome found on ultrasound. Pregnancy terminated at 25 weeks gestation).
- Smith-Lemli-Opitz syndrome (characterized by multiple birth defects, intellectual disabilities and behavioral disorders).
80 to 90% of fetuses with trisomy 13 die in utero. Half of the children reaching term die within three months of their birth.
As the risk of recurrence is very high, it is advisable to perform a karyotype by trophoblast sample the next pregnancy from 12 weeks of pregnancy, this sample is a BVC (chorionic villus biopsy). Only the risk of trisomy 13 is increased, the risk of other chromosomal abnormalities remains unchanged.
Trisomy 9 is a congenital chromosomal disease caused by the presence of an extra chromosome for the 9th pair.
The complete and homogeneous form is extremely rare, causing spontaneous abortion in 80% of cases, and otherwise leading to death within hours of birth.
Mosaic forms are comparatively less rare (200 cases described in the literature) and may be viable, the consequences depending on the proportion of cells affected. The syndrome was first described in 1970 by the French geneticist Marie-Odile Rethoré.
The presence of additional genetic material due to a partial trisomy 9 p leads to various symptoms in people with Rethoré syndrome , although not all features or not all features are present in a person to the same extent. Some of the physical characteristics can already be recognized during ultrasound examinations as part of prenatal diagnostics .
The most common features include:
- Heart defect
- White spots ( golf ball phenomenon in the heart)
- Retardation of motor development
- Delay in bone maturation
- Short stature (below average growth in length)
- Microcephaly (a comparatively small head) with vertical overdevelopment ( scaphocephalus / long skull ), but still a fairly broad head
- Cerebellar malformations
- Enlargement of the cerebral ventricles
- Dandy Walker Malformation
a comparatively small interpupillary distance ( hypotelorism ) and comparatively small eyes (microphthalmia)
high, arched forehead
short, broad nose
deep set, sometimes deformed (dysplastic) ears
small crescent-shaped skin folds at the inner corners of the eyes (epicanthus medialis)
- Invagination of the eyelid edges
outward sloping eyelid axes (the outer corners of the eyelids are lower than the inner corners of the eyelid)
Sinking of the eyeball into the eye socket with reduced vision (enophthalemia / nanophthalmos)
mandibular retrognathia = backward displacement of the lower jaw
Cleft lip and palate
- Neural tube malformation
Special features of the nails (e.g. complete whitening of nails as a result of air retention, can also appear as pinhead-sized spots, crescent-shaped horizontal stripes or alternating wide horizontal stripes)
special position of the fingers and / or feet (bent / in flexion position)
- Malformations in the area of the urogenital tract (this includes all organs that are used for the formation and excretion of urine or sexual reproduction, e.g. the internal and external genital organs , the kidneys , etc. / in boys with trisomy 9, for example, often lag of one or both testicles in the abdominal cavity or in the inguinal canal / cryptorchidism)
- Diaphragmatic hernia (diaphragmatic perforation)
- Calcium deposits in the liver
single umbilical artery (singular umbilical artery)
mostly severe cognitive disability
However, none of these symptoms are conclusive enough for a clear diagnosis , even if some of the special features occur in combination with one another.
A diagnosis is still only possible by examining the chromosomes themselves. Prenatal methods are in particular amniocentesis or chorionic villus sampling or the chromosome analysis that follows these procedures.
The Pätau syndrome (trisomy 13), Edwards syndrome (trisomy 18), Wolf-Hirschhorn syndrome and triploidy are possible differential diagnoses .
Prognosis and therapy
No form of trisomy 9 is causally curable. A therapy is therefore possible only insofar as certain symptoms by medical – therapeutic can reduce or offset methods. So far, many children with trisomy 9 have died during pregnancy or a comparatively short time after birth . In children who live longer, a mosaic trisomy 9 can usually be found and, depending on the proportion of disomeric cells , the prognosis is often more favorable, whereby it also depends on which physical characteristics are present in which manifestations and how they can be treated or how they are treated become. The cognitive Impairments are generally classified as severe.
Warkany syndrome, also called trisomy 8
Warkany syndrome, also called trisomy 8, is a congenital chromosomal disease caused by the presence of an extra chromosome for the 8th pair.
People with trisomy 8 mosaic disease may live like people with trisomy 21, with symptoms and physical abnormalities being roughly the same1,2, while fetuses with complete trisomy 8 very rarely come to term and die in utero.
As with trisomy 21 and trisomy 13, the risk increases with maternal age.
Frequency of occurrence
Trisomy 8 is one of the rare chromosome peculiarities. It occurs sporadically (sporadically, randomly), around 120 cases have been documented. Trisomy 8 is predominantly a mosaic (mosaic trisomy 8 / trisomy 8 mosaic syndrome). Both boys and girls can be born with trisomy 8.
Common signs before birth (prenatally)
In the course of the continuously developing possibilities of prenatal examinations (prenatal diagnosis), some peculiarities have been documented that can be found comparatively often in unborn babies with trisomy 8.
The signs that can indicate the presence of trisomy 8 in the unborn child, especially in combination with one another, and which can sometimes be recognized by means of ultrasound examinations , include, for example:
Malformations of the kidneys , enlargement of the renal pelvis
Skeletal malformations (tetramellia)
Bending of the spine with an outward curve to the front ( scoliosis , lordosis, kyphosis)
two or more consecutive vertebrae are completely or partially fused together (block vertebrae)
slight bending of the little finger in the direction of the ring finger (clinodactyly) with simultaneous shortening of tendons and tendon sheaths, which make a complete extension of the respective finger impossible (camptodactyly)
a comparatively small mouth – chin region ( mandibular retrognathy ) with a shortening of the lower jaw
Short fingers (brachydactyly)
narrow iliac scoop
Missing or malformation of the kneecaps (aplasia or hypoplasia of the patella)
Fluid build-up in the neck area (high neck transparency)
However, none of these symptoms are conclusive enough for a clear diagnosis , even if some of the special features occur in combination with one another.
Up until now, a diagnosis can only be made by examining the chromosomes themselves. Prenatal methods are in particular amniocentesis or chorionic villus sampling or the chromosome analysis that follows these procedures. Particularly with the chorionic villus sampling, it must be borne in mind that a mosaic trisomy 8 can also occur in the placenta , and the baby does not have a fetal mosaic and that mosaics are not always recognized during the other chromosome examination.
Common signs after birth (postnatal)
After birth , most infants with trisomy 8 have different physical characteristics that make what is known as a suspected diagnosis possible. These include:
congenital joint stiffness (arthrogryposis)
often spina bifida occulta
Special features of the soles of the feet (particularly noticeable grooves on the soles / plantar furrows)
a comparatively large distance between the first and second toe ( sandal gap / sandal furrow )
many and deep furrows in the palms of the hands ( palmar furrows )
Four-finger furrow (in approx. 75 out of 100 children)
comparatively deep, large and long ears
underdeveloped (hypoplastic) fold that lies opposite the rim of the auricle ( anthelix )
narrow, sloping shoulders
Special features of the number and width of the ribs
surplus (accessory) nipples ( nipples )
high, narrow palate
full, plump lips, everted lower lip
comparatively small eye relief ( hypotelorism )
One or both eyelids drooping , with the upper eyelid more likely to be affected ( ptosis )
Squint ( strabismus )
wide nose , often upturned nostrils (nares)
often above average weight
increased tumor risk
mild to moderate cognitive disability
Other syndromes with arthrogryposis can be used as differential diagnoses .
Trisomy 8 cannot be cured causally, only the symptoms can be treated. The clinical picture is quite variable, especially with mosaic trisomy 8, and people are also known to have hardly any abnormalities.
A prognosis for physical development depends on which physical characteristics are present in which form and how they can be treated or how they are treated.
The cognitive impairments are generally classified as mild to moderate, in people with mosaic trisomy 8 they are often milder and very variable in severity. With a significantly lower proportion of trisomeric cells, it is also possible to achieve the usual intelligence.
Down syndrome affecting the sex chromosomes
Since trisomy is defined by the presence of an extra chromosome in the karyotype, all chromosomes can be involved, including sex chromosomes. Also there are trisomies affecting the pair of X or XY chromosomes. The main consequence of these trisomies is to affect the functions of the sex chromosomes, including the levels of sex hormones and the reproductive organs.
There are three types of sex chromosome trisomy:
- XXX (triple X)
- XXY (Klinefelter syndrome or 47)
- XYY (“double Y” or Syndrome 47)
(A)Triple X syndrome
Triple X syndrome is an aneuploidy of the sex chromosome in women. It is characterized by the presence of an additional X chromosome in each cell of a woman (therefore homogeneous). The syndrome is also called syndrome XXX, trisomy X, triplo-X, 47xxx or aneuploidy 47, XxxxX. This chromosomal variant results from the production of a diploid gamete during meiosis.
Trisomy-X appears during the division of the parents’ gametes. About 1 in 1,000 women is affected. The 10% of women who are diagnosed (among those with trisomy-X) and who show symptoms are typically larger than average.
Very often, trisomy X does not cause medical problems or specific traits, and goes undetected. Women with this syndrome are generally taller than average, may have irregular menstrual cycles, and have a greater risk of having learning difficulties, especially language difficulties, rarely including mental retardation. They can show emotional instability. Researchers do not yet fully understand the apparent link between an extra copy of the X chromosome and learning difficulties in some girls and women, but it is established that their large size is due to the presence of the SHOX gene (gene responsible); size, present on the short arm of X, and therefore here in 3 copies) which is then over-expressed. About 10% of affected women develop kidney problems. However, these characteristics vary greatly between affected individuals. On the other hand, most women with triple X syndrome have normal sexual development and are able to conceive healthy children.
Caused like the vast majority of trisomies as a result of a poor distribution of chromosomes during gametogenesis, this poor distribution can occur both during oogenesis (anaphase I or anaphase II) and during spermatogenesis (anaphase II only , when the paternal double X chromosome splits into two single X chromosomes and both copies start from the same side of the cell). Like any trisomy or more generally all aneuploidies, their occurrence increases with the age of the mother.
(B) Klinefelter syndrome or 47, XXY
Klinefelter syndrome or 47, XXY is an aneuploidy characterized in humans by an additional X sex chromosome. The individual then presents two X chromosomes and one Y chromosome, ie 47 chromosomes instead of 46. The individual is then male, but infertile. Its chromosomal formula is written “47, XXY”.
This syndrome was described in 19421 but its etiology was then unknown. It was in 19592 that the chromosomal origin of this syndrome was discovered.
The origins of this peculiarity are found during the meiosis of the gametes of the subject’s parents, when the sex chromosomes are not distributed normally. Another group called “mosaic” finds its origins during mitosis. This group accounts for roughly 10% of Klinefelter syndrome cases. The so-called “mosaic” individuals do not have all the cells affected by the chromosomal characteristic and are therefore for some able to have children.
Many individuals carry this karyotype without being really affected (apart from their infertility). About one in every 500 to 1,000 male births is a carrier of this syndrome. Karyotype 47, XXY (80% of Klinefelter cases) is to be distinguished from karyotypes 48, XXXY, 48, XXYY and 49, XXXXY and other mosaics which then present consequences other than those mentioned above and which constitute 20% of cases.
Less than 10% of these syndromes are diagnosed before adulthood and it is likely that only a quarter of cases are actually detected.
Under the name of Klinefelter syndrome we group together all or part of all of the following symptoms, a variability of expression being often observed and all the problems of life that cannot be linked to this syndrome: size on average larger than the siblings, possible delay in puberty, possibility during childhood of learning disabilities of language or reading, size of the testicles smaller from puberty, possibility in adolescence if there is a lack of testosterone of a low hairiness, lack of muscle tone, development of mammary glands or gynecomastia, brittle tooth enamel and osteoporosis in adulthood.
The atypical expression of this syndrome therefore explains the frequent delay in its diagnosis, which is often done only as part of a search for sterility.
Typically there is a biological picture of hypergonadotropic hypogonadism, with, in adults, a normal or low concentration of testosterone and an elevated level of LH and FSH5.
The diagnosis is made using the karyotype but it is much more difficult in the event of mosaic.
Overall mortality is increased, mainly from cardiovascular, neurological or pulmonary causes.
The risk of breast cancer is increased as well as that of thromboembolic disease, diabetes or osteoporosis.
For children with learning difficulties, the establishment of early and traditional care in speech therapy and occupational therapy can help.
Hormonal treatment with testosterone from puberty may be offered. It improves symptoms (without solving the problem of infertility) and can prevent some late complications like osteoporosis.
In the event of significant and disabling gynecomastia, plastic surgery may be offered. Likewise, one can perform an excision of the small testicles in those who have difficulty accepting this condition, with the installation of testicular prostheses.
The management of infertility is carried out by teams of medically assisted procreation (AMP), which will determine the degree of infertility and the various possibilities that result from it (in vitro fertilization and intracytoplasmic sperm injection; artificial insemination with donor; adoption). Azospermia (absence of spermatozoa in the ejaculate) is sometimes not the witness of the absence of sperm production and intratesticular samples have been taken.
The European academy of andrology published recommendations on Klinefelter syndrome in 2020.
(C) Syndrome 47, XYY (“double Y”)
Syndrome 47, XYY (“double Y”) is a human aneuploidy, it is more particularly a trisomy explained by the abnormal presence of a second Y chromosome. Usually the human karyotype is composed of 46 chromosomes or 23 pairs, in the case of this syndrome there are 2×23 + 1 (2n + 1) chromosomes, corresponding to a trisomy called disomy Y (presence of 2 Y chromosomes).
The use of the term “syndrome” is questioned by some geneticists. Those affected indeed have a normal male phenotype and many of them do not even know their karyotype.
This syndrome is also called Jacob’s syndrome or killer syndrome.
Most of the time, the presence of an extra Y chromosome does not come with any unusual physical traits or medical problems. In childhood, children have accelerated growth with, on average, a final height that will be 7 cm larger than expected. A few cases of severe acne have been detected but dermatologists specializing in acne problems are now questioning the existence of a relationship with 47-XYY.
Prenatal and postnatal testosterone levels are normal. Many people with the syndrome have normal male sexual development and fertility. Since XYY syndrome is not characterized by any distinctive physical features, the abnormality is often only noted during genetic analyzes performed for another purpose.
Children with 47, XYY syndrome have a higher risk of developing learning problems (50% higher) and delayed language development. Conversely, a national survey conducted in 2004 in the United States by the “Center for Disease Control and Prevention” indicates that 10% of children affected by this genetic defect have learning problems.
As with children with abnormalities 47, XXY (males) and 47, XXX (females), the IQ test scores of children with syndrome 47, XYY are on average between 10 and 15 points below their brothers’ results. and sisters. However, this difference (12 points on average) is that which is usually observed between children of the same family. Out of 14 cases of children from families of high socioeconomic background, the IQ for 6 of them was between 100 and 147 with an average of 120. Among the 11 children who had siblings, 9 had siblings who performed better in school, but in one case their results were equal and in the last case they were even lower than the child’s.
Developmental delays or behavioral problems are also observable and these people tend to be more aggressive. But these characteristics have great variability in the affected population, are not specific to people with 47, XYY syndrome, and are not expressed differently from people with a typical 46, XY male karyotype.
D47, XYY is not an inherited disease, the anomaly appears randomly during the formation of germ cells. Improper disjunction of gonosomes during anaphase II of meiosis can cause germ cells to appear with an extra copy of the Y chromosome. If one of these atypical sperm is involved in fertilization, the child will have an extra Y chromosome in all of its cells.
In some cases, the error occurs at the level of postzygotic mitosis cell division at the start of embryonic development. This can produce a mosaic between 46, XY and 47, XYY.
The frequency of observation for syndrome 47, XYY is 1 per 1000 births to boys1. The age of the parents has no influence on the frequency of appearance.
The first documented case of a person with a 47, XYY karyotype was reported by Avery A. Sandberg and colleagues at the Roswell Park Memorial Institute in Buffalo, New York, in 1961. The discovery was unintentional in a subject of 44 years old, 183 cm tall and with normal intelligence, while doing a karyotype analysis because his daughter had Down’s syndrome.
47, XYY was the last of the sex chromosome aneuploidies discovered (47, XXY and 45, X were discovered two years earlier and 47, XXX in 1959). Even the very rare case of 48, XXYY had been revealed a year earlier in 1960. Visualization of aneuploidy affecting the X chromosome can be achieved by the absence or presence of “female” heterochromatin (Barr’s corpuscle). in the nuclei of interphase cells during the study of an oral smear (technique developed ten years before the report of the first sexual aneuploidy).
The analogous technique for visualizing aneuploidies on the Y chromosome by the excessive presence of “male” heterochromatin was not developed until 1970 (ten years after the first aneuploidy on the sex chromosomes).
Photo credit (main photo): Uncomfortable Revolution