The 15 most important chromosomal syndromes

The genetic material available to any living being is the "manual of instructions" that all the cells of your body will use in order to operate their effects on it. It is the foundation of who we are, because in it the heritage of our ancestors is kept alive.

The human being has two copies for the chromosomes that it has, adding up to a total of 46, and its nature being diploid. In the event that there is no variation in this number or an aberrant mutation in one or more units, the gestational process ends (in just a few months) with the labor and delivery of a living being healthy.

However, a small change in such a fragile balance can be dramatic, and give way to phenomena known as chromosomal syndromes. In this article we will review the most common, both due to excess or deficit of chromosomes and due to alterations in their structure.

• Related article: "Differences between DNA and RNA"

Chromosome syndromes

Chromosomal syndromes are the result of abnormalities in the structure of human DNA, both in a quantitative sense (the number of chromosomes exceeds or it does not reach 46, which is the "absolute quantity" available to our species) as qualitative (there is a mutation in the structure of the chromosome). Depending on the position or alteration in question, the consequences vary greatly. In this text we will address which are the main chromosomal syndromes in both cases.

Quantitative genetic alterations (by number of chromosomes)

Human cells are diploid in nature, so each chromosome exists in an even number. Every gene would therefore have its own copy, located somewhere on these chromosomes.

To form a zygote, each of the parents (male and female) contributes a haploid gamete, and through their combination a new living being (or potential) is forged with 46 chromosomes, in which the genetic background of the two is included. In this process, it sometimes happens that this number is altered, resulting in disturbances that can make survival unfeasible even in the short term.

The most common case of quantitative alteration of the genes are trisomies, especially those of the 21st pair and those of the sexual one. In both cases, the organism usually stays alive after birth, something that does not always happen with other pairs. In this case it is said that one of the chromosomes has three copies instead of two, adding up to 47 in total (instead of 46). Another situation is that which occurs within monosomies, in which one of the pairs remains devoid of the chromosome that would accompany it, adding a total of 45 (instead of the relevant 46). Let's look at some examples of this type of genetic syndromes.

1. Down's Syndrome

Down syndrome would arise as a result of the presence of an extra chromosome in pair 21, which is why it is known as trisomy 21. It is, without any doubt, the most common cause of intellectual disability with a genetic basis, since its prevalence world-wide is around 0.1% (although it may increase if the mother is forty years or older at the time of birth). Birth). Until relatively recently, it was a circumstance that could dramatically limit life expectancy and significantly reduce the well-being of those who presented it; since he lives with some congenital problems in the heart, respiratory and intestinal systems.

The face of people with this syndrome has a well-known and recognizable pattern, which is characterized by epicanthic folds on the inner edge of the eye and a flattened nose. Both the palate and the maxilla do not present the development that is required for the containment of the tongue within the oral cavity, so it projects outwards. The fingers of the hands have a hypoplasia of the middle phalanx of the little finger, and the palm shows a transverse fold (dermatoglyph very similar to that usually found in some species of primates).

Intellectual disability is the central feature of the syndrome, with IQs ranging between 25 and 50. However, the ability to live autonomously will depend on the way the parents articulate their environment and / or the stimulation they receive. People with the chromosome alteration in question are usually cheerful and refuse violence. In addition, men who "suffer" are completely sterile, although women are not. The children of the latter have a 50% probability of transmitting the condition to their descendants.

Generally slow fetal development is observed that alerts of the possible presence of the same, which can be detected by means of the amniocentesis test (extraction of a puncture sample of amniotic fluid for laboratory analysis, which should be carried out by medical personnel correspondent).

• You may be interested: "6 activities for children with Down syndrome"

2. Edwards syndrome

Edwards syndrome is the result of a trisomy in the 18th pair. Thus, an extra chromosome would be found at this location, as described earlier in Down syndrome (for 21). In this case, a series of more severe alterations would be appreciated, which generally imply death in the first months after birth. Survival until adulthood or adolescence would be very infrequent, and always conditioned by the emergence of very deep physical and mental problems.

At birth, a very low weight is evident, and also the occurrence of deformities of both the face and head. Of all of them, the small size of the latter and the low location of the ears stand out, as well as an extraordinarily thin upper lip. It is not unusual for the palate and the lips themselves to have a central cleft. The hands also have major alterations, highlighting excessively long fingers and the deficient development of the thumb. The feet are of reduced length, and also its bridge is hardly noticeable or non-existent.

In a significant percentage of cases, there is a problem in the visceral anatomy known as exonphalos, in which a part of the intestine implants in a sac outside the abdomen (which is life-threatening in childbirth). Other frequent physical difficulties in this syndrome are cardiac, renal and respiratory, as well as deformities in the locomotor system and infections of recurrent incidence in the urinary tract.

The low life expectancy makes it extremely difficult to study the implications on the sphere of cognition, although The little evidence that is available points to the serious compromise of the intellect and the capacity to learn.

• You may be interested: "Edwards syndrome (trisomy 18): causes, symptoms and types"

3. Patau syndrome

Patau syndrome is the result of a trisomy in the thirteenth pair. Of all the pathologies of this nature, the one that concerns us is perhaps the most severe, since up to 95% of Children die during their gestation (and those who survive do not survive the first few days in most cases).

Those who suffer from it present obvious malformations in the appearance of the face, in which there is a very short distance between the eyes, which are also usually small and / or deformed. In some cases there may be only one eyeball (cyclopia) or the child may not have either of the two. A coloboma is rarely seen, in the form of holes where the pupils should be. Other characteristic features are on the nose (absence of the nasal skeleton) and on the lips (cleft cleft).

The brain is, without a doubt, the vital organ where the most important problems are found in the case at hand. The most common is that it occurs holoprosencephaly, that is, a total absence of the frontal lobe and a "fusion" of the hemispheres.

At the motor level, the total loss of muscle tone stands out, and an absence of response to environmental stimulation. If the child survives beyond the first week, there are psychomotor retardation and very great obstacles to reaching basic developmental milestones.

Other frequent physical characteristics in the syndrome are postaxial polydactyly (one finger supernumerary after the fifth), serious heart problems and alterations at the level of the system urogenital.

4. Turner syndrome (Monosomy X)

Turner syndrome is expressed in women who have a partial or total absence of an X chromosome. Its phenotypic manifestation is subtle among those that survive the gestation process. 90% of those affected die in the third trimester, constituting up to 10% of spontaneous abortions within such time period. One in 3000 people born lives with this syndrome, and occasionally without knowing it for many years.

Pubertal delay is common along with amenorrhea (absent menstruation), and sensory organ problems: recurrent otitis media that can lead to hearing loss, strabismus, etc. It is common to see significant changes in the spinal cord (scoliosis) and in the hip, the which tend to hinder ambulation, as well as cubitus valgus (deviation "out" of the angle of the elbows). In some cases, congenital lymphedema becomes evident, that is, problems for adequate drainage of part of the lymphatic system. The ability to be fertile is also impaired, and may require assisted reproduction.

Affected women show a series of particular physical expressions, most of them very discreet. Back hairline may be raised, neck takes webbed folds, the ears are in the natural position but slightly disfigured / rotated and the teeth are too crowded in the oral cavity. In addition, the palate may be narrower than conventional and there is an excessive distance between the nipples (which is associated with an extensive rib cage), along with a short stature.

Women with this chromosomal syndrome may be at increased risk of major congenital diseases, which affect the different organs and systems, namely: kidney and heart malformations (alterations in the aorta and bicuspid valve) or autoimmune thyroiditis, to name an example.

5. Klinefelter syndrome (47XXY)

Klinefelter syndrome is caused by a duplication of the X chromosome (disomy X). It is exclusive to males and is characterized by poor masculinization, especially during adolescence. The underlying cause is the alteration of the hypothalamic pituitary gonadal axis, which "mobilizes" very low levels of testosterone and insufficient development of primary / secondary sexual characteristics. In these cases, the volume of the testicles would be small and there would also be azoospermia (low sperm production).

Before reaching this vital stage, however, some abnormalities in the physical appearance may appear suggesting that this genetic condition is suffered. Simple anatomical observation reveals a small head circumference and a particular bony distribution (wide hip and narrow back).

Growth is also irregular, with slowing in the first years and acceleration from the fifth or eighth year of life, especially due to the extraordinary development of the lower limbs (by which they would end up reaching a normal or even tall size).

At the neurological level, reduced muscle tone is observed, which conditions gross motor skills (clumsiness) and alters the structure of the spine due to laxity of the ligaments (kyphosis or scoliosis). Some deformity may also appear in the ribs and vertebrae found in the lower back region (lumbosacras), being particularly common the presence of pectus carinatum (projection of the rib cage outwards, adopting a shape similar to the keel of a boat). Finally, the feet are usually flat and coexist with clinodactyly (disturbance in the angle of the toes due to specific involvement of the fifth metatarsal and metacarpal).

At the cognitive level, alterations are observed that become very important, and especially notable when the demands of academic life increase. Intellectual disability ranges from mild to moderate.

6. Double Y syndrome (47XYY)

In this case, the causative genetic aberration is the presence of an extra Y chromosome, which fundamentally generates a series of alterations in hormonal dynamics. A high percentage of those who suffer from it (men) do not live with problems of any kind, although others do express complaints that must be evaluated and addressed therapeutically. Almost all of these patients have intelligence at the statistical threshold of normality, but they suffer from affective difficulties (such as anxiety and / or depression), and a high incidence of attention deficit hyperactivity disorder has been found.

At an evolutionary level, it stands out a noticeable delay in the acquisition of speech and motor milestones (crawling, first steps, etc.), which can predict the subsequent emergence of a learning disorder when accessing academic life. Muscle tone can be weak, with essential tremors in the hands and feet, and even with significant presence of motor tics.

In a very low percentage of cases, microcephaly (small head) and hypertelorism (a pronounced separation between the eyes), as well as malformations in the urogenital system, among which the following stand out: large testicles excessively large, cryptorchidism (testicles deposited within the abdominal cavity and not descending into the scrotal bag) and hypospadias (location of the urethra in a position anomalous).

They tend to grow taller than average in adulthood, and acne is common late into their lives.. Higher risks have been described for asthma, infertility, and autism; as well as for hydrocephalus (excessive accumulation of cerebrospinal fluid due to high production or low drainage).

Although for a time it was postulated that they could be aggressive subjects, the truth is that there is no basis empirical evidence to support that idea (in fact it was known for a long time as the "syndrome of supermale "). In general they can be adapted correctly to daily demands.

7. Pallister Killian syndrome

This syndrome is associated with the presence of an extra chromosome in pair 12. It is a severe condition, which precipitates the death of the newborn during the days following delivery.

Survival rarely lasts for a few years, and when it does, it most often involves living with a myriad of varied and serious physical and / or mental problems. The intellectual deficit is notable, and does not allow to acquire the language or almost any other of the developmental milestones.

The face of those affected has a peculiar physiognomy, which contributes to its diagnosis. More specifically, a flat profile is observed, with a wide forehead and an excessive separation between the eyes. The eyelid folds are barely noticeable, the cartilaginous projection of the nose is very short and with upward-facing orifices. The wrinkles located on the side of the mouth would adopt downward trajectories, while his upper lip would stand out for its excessive thickness. With the passing of time, these features are accentuated and aggravated.

Both the neurological and cardiac systems are severely compromised. The first case involves severe intellectual deficit, muscle atony, and tonic and clonic seizures; while the second would precipitate notable malformations of the ventricular septum (25% of the time). At the skeletal level, the substantial shortening of the limbs or the reduced size of the hands and feet, as well as the deficient formation of the nails in both limbs, are of importance.

Qualitative genetic alterations (by chromosome structure)

Sometimes there is a loss / gain of genetic material, which involves the structural alteration of the chromosome. It could be a deletion (some section of it disappears), or it could be expressed as a translocation (the portion would not be lost but would be attached to another chromosome different from the one that originally corresponded).

What is known as inversion also usually occurs, in which the "piece" of chromosome remains in its original position although oriented in the opposite direction; or duplication, in which the same segment replicates itself twice. Let's look at some cases of this type of syndromes.

1. Wolf Hirschhorn syndrome

This syndrome is caused by a partial deletion of the short arm of chromosome 4, and it is a pathology that seriously affects both the body and cognitive development. It is usually suspected from a marked delay in normal physical growth, which is accompanied by seizures and the presentation of pathognomonic facial features.

The shape of the face has received the name of "helmet of Greek warrior". It is characterized by a flat and wide nasal bridge, with a short distance between the nose and the upper lip. The mouth projects downward, the jaw is small, and there is some abnormality in the external structure of both ears. The eyes are usually far apart from the central axis of the face, and there are often very pronounced asymmetries. Only on very rare occasions is the cranial perimeter small (microcephaly), and there is evidence of an alteration in the alignment of the teeth or a cleft palate.

At a body level, short stature stands out, which could be associated with difficulties in feeding during the first years. Perhaps this is also why the muscular structure is usually scrawny, with a weight well below that which would be predicted by chronological age, and delayed motor development. All of it has an impact on the spine, both due to kyphosis and scoliosis (deviation from it). Other striking alterations are excessively dry skin and the occasional appearance of specks of darkened pigment.

In these cases, intellectual disability is in the moderate to severe range, with a special impairment of verbal abilities.

2. Cri du Chat syndrome (5p)

This chromosomal syndrome It is the result of the deletion of the genetic material located on the short arm of chromosome 5. Sometimes it is also labeled "Lejeune syndrome". Its incidence is much higher in women than in men (3: 1), and it is estimated that approximately one in 20,000 / 50,000 newborns suffers from it. He lives with notable organic and cognitive comorbidities, which limit autonomy or quality of life.

In the neonate a tendency to high-pitched crying is common (similar to that emitted by a cat) as well as abnormalities in the larynx and central nervous system. The first months are marked by difficulties in sucking and feeding, with severe cyanotic crises (respiratory distress) and generalized jaundice (yellowing of the skin). Weight tends to be low at the time of delivery, in which microcephaly, lax muscle tone, and delayed psychomotor development are usually evident.

The face, as in other syndromes whose origin is genetic, also shows a series of peculiarities. The face is rounded and with flat cheeks, showing also an epicanthic fold (covering the inner part of the eyes, the one closest to the nasal septum). Both the jaw and chin are not very prominent (micrognathia) and the ears are in a relatively low position. Divergent strabismus (towards the outside of the eyeball) is common, especially in adolescence, as well as the fact that the corner of the lips slopes significantly downwards.

Fingers and toes are shorter than usual. In addition, both the one and the other show slight deformities, and gray hair usually appears at an early stage of development. The presence of alterations in the heart can put your life at serious risk, and intellectual disability (usually of great intensity) limits independence in elementary areas and in basic learning abilities.

3. 22q11 deletion syndrome

It is a genetic syndrome that has its origin in a loss of the 22q11.2 region, on chromosome 22, which helps an embryo to develop important parts of the body: the thymus, the parathyroid glands, the heart, the palate and multiple regions of the brain (neural crest). It affects one in every 4,000 new births and has many forms of expression, both physically and psychologically.

The most relevant of all of them are those that are detailed: heart abnormalities (50-75%), cleft palate (60%), hypocalcemia due to poor calcium regulation (50%) and predisposition to autoimmune processes. All of them have a relationship of relative independence, so they can be presented in a single or mixed way.

With regard to cognitive and psychological alterations, motor and learning difficulties stand out, as well as the delay in the acquisition of language (80%) and the deficit in specific dimensions (working memory, speed for processing sensory information and reasoning abstract). Some disorders, such as those that fall into the category of anxiety, attention deficit hyperactivity disorder and / or OCD (obsessive compulsive disorder); they are more frequent in people with this syndrome than in the general population. In addition, up to 20% suffer from schizophrenia at some point in life.

4. Fragile X syndrome

Fragile X syndrome occurs after mutations in the FMR1 gene, which has the purpose of "instructing" the production of FMRP proteins, from which it is possible to build a connection between neurons (synapses). In addition, a portion of the DNA known as CGG is replicated in these cases in an "aberrant" way, exceeding 200 iterations (when the usual would be between 5 and 40). It is much more common in boys (one in 4,000) than in girls (one in 6,000-8,000).

His face acquires particular features, with which its detection is possible: a narrow and long face, large ears, a prominent jaw and a broad forehead. The feet are usually totally flat, without a bridge, and the toes have extraordinary flexibility. In a high percentage of cases, endocrine-based macroorchidism (large testicles) is observed.

People with fragile X syndrome have a moderate to mild intellectual disability, with delayed language (especially from the second year) and limitations when it comes to learning. It is related to a myriad of psychological disorders, such as anxiety and the autism spectrum, as well as ADHD (attention deficit hyperactivity disorder) and / or impulsivity. Up to 10% of the total suffer epileptic seizures that require an independent approach.

5. Robinow syndrome

Robinow syndrome is very rare, and also extremely severe. It is the result of a mutation in the ROR2 gene and one of the most common causes of genetic dwarfism.

In addition to the short stature, arms and legs of short length are observed (especially in the first ones), which which also extends to the fingers and toes (often fused by syndactyly). The spine and rib cage are often disfigured, causing severe pain and difficulties with proper motor skills..

At birth, it is common for the sexual organs to show substantial undifferentiation, which makes the process of assigning a sex to the boy or girl difficult. Renal / cardiac involvement is also common (15%), and in some cases fatal.

The face is characterized by a significant distance between the eyes, a small nose, a broad forehead and prominent lips and inverted V-shaped lips can reveal the gums and teeth to the outside superiors. The lower lip may also appear split, and causes alterations in the oral cavity such as ankyloglossia (union of the lower part of the tongue with the base of the mouth). The teeth are irregular in shape, occupying the space reserved for the hard palate on many occasions. The eyes may be projected outwards due to a malformation of the lower eyelid (false exophthalmia), which could require surgery.

6. Prader-Willi syndrome

This syndrome is caused by the lack of a gene on chromosome 15. Sometimes it is a mutation, while other times it is the absence of the paternal contribution or the presence of two genes exclusively from the mother. It generates very diverse physical, mental and behavioral problems.

This condition became popular in its day for causing the persistent and voracious feeling of hunger, with hyperphagia (large intakes) and absence of a feeling of satiety, which could precipitate extreme overweight together with the health problems that could be associated with it. Likewise, it seems that the child is always tired, with difficulty moving and with a soft or barely audible cry. These problems would hinder the correct sleep process, limited by obstructive apneas and micro-awakenings, with daytime sleepiness of secondary origin.

At the body level poor muscle tone is also observed, with absolute atony during the suspension of the child in his arms. Visual problems are common, especially myopia, and also congenital hypopigmentation (grayish color of the eyes, hair and skin). Finally, the presence of scoliosis and small hands / feet stands out, as well as defects in the genitals (both in the case of boys and girls). On the face, it is often noticed that the eyes acquire an almond shape, and that the upper / lower lips lack volume. The head tapers where the temples are located, and the mouth projects noticeably downward.

These children have a cognitive impairment to consider, and an intellectual disability that is on the threshold of mild to moderate. The most common problems occur in functions such as planning, problem solving, and abstract reasoning. Speech is often delayed, with poor articulation of phonemes.

The most common behavior problems involve Irresistible bouts of bad temper, tantrums, and difficulty tolerating changes in the environment. Obsessive-compulsive habits, as well as anxiety and depression, could also be present, along with persistent scratching of the body (excoriation).

7. Waadenburg syndrome

This syndrome is caused by mutations in the EDNRB, EDN3 and SOX10 genes; those that are associated with the production of melanocytes and nerve cells in the intestines. Apparently, the alterations of the last of them are those that are related to more severe forms of this congenital problem.

It is a syndrome that causes a whole series of pigmentary abnormalities (white lock, pale eyebrows and eyelashes, and light "spots" distributed on the surface of the skin). In many cases there may be heterochromia (different colored eyes), as well as sensorineural deafness (usually bilateral) and a persistent bowel obstruction along with distended abdomen. Also it usually presents with anosmia (loss of olfactory ability) and malformations in the temporal bones of the skull.

8. William syndrome

William syndrome, almost exclusive to girls, is the result of micro-erasures of chromosome 7. Many authors propose that there are two forms, one of them more severe than the other. It happens in at least one in every 7500 births.

The face of those affected adopts a series of features that have earned the nickname "goblin face". In these cases, an elongated shape is seen, with notable swelling in the periocular region (around the eyes). The forehead is broad and the nose is usually flat, with a subtle chin and prominent lips. One of the most striking details, which is not always present, are the star-shaped irises (star-shaped). The teeth are placed in anatomically inappropriate positions, which affects the production of understandable verbal language.

The problems in the body are disparate and important. Heart failure (80%), pulmonary involvement (80%) and endocrine disorders may concur. Weight at birth is usually low, and it is not uncommon for excess calcium to occur during childhood. Digestive problems can be present throughout the life cycle, with a special incidence of vomiting and recurrent constipation. Muscle tone is poor, which contributes to joint deformities during the transition process from childhood to adolescence. In adulthood, hypertensive crises often emerge.

Although it is usually evident that there is a degree of intellectual disability (slight / moderate), language skills are usually good, and even located above average. Despite this, spatial cognition tends to have deficient characteristics, and sleep disorders appear during childhood and adolescence (irregular pattern). A very high percentage (95%) develop hyperacusis, which translates into an exaggerated response to loud sounds.

Bibliographic references:

• Elkarhat, Z., Zarouf, L., Razoki, L., Aboulfaraj, J., Nassereddine, S., Cadi, R., Rouba, H., and Barakat, A. (2018). Chromosomal Abnormalities in Patients with Intellectual Disability: A 21-Year Retrospective Study. Human Heredity. 83, 274-282.
• Theisen, A. & Shaffer, L. (2010). Disorders caused by chromosome abnormalities. The application of clinical genetics, 3, 159-74.