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

The human being has two copies for the chromosomes he has, making a total of 46, and being diploid in nature. If 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 birth of a healthy living being.

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

Chromosomal syndromes

Chromosomal syndromes are the result of abnormalities in the structure of human DNA, both in a quantitative (the number of chromosomes exceeds or falls short of 46, which is the “absolute number” available to our species) and qualitative (a mutation in the very structure of the chromosome) sense. Depending on the position or the alteration in question, the consequences vary greatly. In this text we will address what 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 its combination a new living (or potential) being is forged with 46 chromosomes, which include the genetic baggage of both . 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 gene alteration is trisomies, especially those of the 21st pair and sexual. In both cases the organism is usually kept alive after birth, which is not always the case with other pairs. In this case, one of the chromosomes has three copies instead of two, making a total of 47 (instead of 46). Another situation is that which occurs within monosomies, in which one of the pairs is deprived of the chromosome that would accompany it, adding up to a total of 45 (instead of the relevant 46). Let’s see some examples of this type of genetic syndromes.

1. Down syndrome

Down syndrome would arise as a result of the presence of an extra chromosome in the pair 21 , which is why it is known as trisomy 21. It is undoubtedly the most common genetically-based cause of intellectual disability, with a worldwide prevalence of about 0.1% (although this may increase if the mother is aged 40 or over at the time of delivery). Until relatively recently, it was a circumstance that could dramatically limit life expectancy and significantly reduce the well-being of those who suffered from it; since it coexists with some congenital problems in the cardiac, respiratory and intestinal systems.

The face of people with this syndrome has a well-known and recognizable pattern, which is characterized by epicanthal folds at the inner edge of the eye and a flattened nose. Both the palate and the jaw do not have the development required for the tongue to be contained within the oral cavity, so the tongue is projected outward. The fingers have a hypoplasia of the middle phalanx of the little finger, and in the palm there is 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 from 25 to 50 . However, the ability to live autonomously will depend on the way in which the parents articulate their environment and/or the stimulation they receive. People with the chromosomal disorder in question are usually happy and refuse violence. Furthermore, men who “suffer” it are all sterile, although not women. The children of the latter have a 50% chance of passing the condition on to their descendants.

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

2. Edwards syndrome

Edwards syndrome is the result of a trisomy in the 18th pair. Thus, an extra chromosome would be found in this location, as described above in Down syndrome (for 21). In this case, there would be a succession of more severe alterations, usually involving death in the first few months after birth. Survival into adulthood or adolescence would be very rare, and always conditioned by the onset of very profound physical and psychological problems.

A very low birth weight is evident, and also the occurrence of deformities in both the face and head . Of all of these, the small size of the latter and the low location of the ears, as well as an extraordinarily thin upper lip, stand out. It is not unusual for the palate and the lips themselves to have a central cleft. The hands also have alterations of great entity, emphasizing too long fingers and the deficient development of the thumb. The feet are of reduced length, and in addition its bridge is hardly appreciable or nonexistent.

In a significant percentage of cases, a problem occurs in the visceral anatomy known as exonphalos, in which a part of the intestine is implanted 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 locomotive system and recurrent infections 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 available points to the serious commitment of the intellect and the ability to learn.

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, given that up to 95% of children die during their gestation (and those who survive do not get past the first few days in most cases).

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

The brain is, without a doubt, the vital organ where the most important problems are found in this case. Most commonly, holoprosencephaly is present, that is, a total lack of frontal lobe and a “fusion” of the hemispheres.

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

Other common physical features of the syndrome are post-tax polydactyly (a supernumerary finger after the fifth), serious heart problems and alterations to the urogenital system.

4. Turner’s Syndrome (Monosomy X)

Turner syndrome is expressed in women who have the absence (partial or total) of an X chromosome . Its phenotypical manifestation is subtle among those who survive the process of pregnancy. 90% of those affected die in the third trimester, constituting up to 10% of miscarriages within this time period. One in every 3000 people born live with this syndrome, and occasionally without knowing it for many years.

It is common for a delay in puberty to occur along with amenorrhea (absent menstruation), and problems in the sensory organs : recurrent otitis media that can lead to hearing loss, strabismus, etc. Significant alterations in the spinal cord (scoliosis) and in the hip are frequently observed, which often hinder deambulation, as well as cubitus valgus (“outward” deviation of the angle of the elbows). In some cases, congenital lymphedema is evident, that is, problems with adequate drainage of part of the lymphatic system. The ability to be fertile is also altered, and may require assisted reproduction.

The women concerned show a number of particular physical expressions, most of them very discreet. The back hairline may be elevated, the neck adopts webbed folds , the ears are placed 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 excessive distance between the nipples (associated with a large rib cage), along with short stature.

Women with this chromosomal syndrome may be at increased risk for major congenital diseases , which affect different organs and systems, namely: renal and cardiac malformations (alterations in the aorta and bicuspid valve) or autoimmune thyroiditis, to name a few.

5. Klinefelter’s Syndrome (47XXY)

Klinefelter syndrome is caused by duplication of the X chromosome (X-diskomy). It is unique to males and is characterized by poor masculinization, especially during adolescence. The underlying cause is the alteration of the gonadal pituitary axis, which “mobilises” 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 physical appearance may appear suggesting that one is suffering from this genetic condition. Simple anatomical observation reveals a small cranial perimeter and a particular bone distribution (wide hip and narrow back).

The growth is also irregular, with slowing down in the first years and acceleration from the fifth or eighth year of life , mainly due to the extraordinary development of the lower limbs (by which they would end up reaching a normal or even high 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 ligament laxity (kyphosis or scoliosis). Some deformity may also appear in the ribs and the vertebrae located in the lower back region (lumbosacral), being particularly common the presence of pectus carinatum (projection of the thoracic cage towards the outside, adopting a shape similar to the keel of a ship). Finally, the feet are usually flat and coexist with clinodactyly (disturbance in the angle of the toes by 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 generates a series of alterations in hormonal dynamics, fundamentally. A high percentage of those who suffer from it (men) do not live with problems of any kind , although others do express complaints that should be assessed and addressed therapeutically. Almost all these patients have an intelligence at the statistical threshold of normality, but suffer from affective difficulties (such as anxiety and/or depression), and a high concurrence of attention deficit and hyperactivity disorder has been found.

On a developmental level, there is a notable delay in the acquisition of speech and the motor milestones (crawling, first steps, etc.), which can predict the subsequent irruption of some learning disorder when accessing academic life. Muscle tone may 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 there is 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: excessively large testicles, cryptorchidism (testicles deposited within the abdominal cavity and not descending into the scrotal sac) and hypospadias (location of the urethra in an anomalous position).

In adulthood they usually reach a height above average, and the presence of acne is common until very advanced stages of 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 empirical basis to support that idea (in fact it was known for a long time as the “supermale syndrome”). In general, they can adapt correctly to everyday demands.

7. Pallister Killian Syndrome

This syndrome is associated with the presence of an extra chromosome in the 12th pair . This 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 deficit on an intellectual level is notable, and does not allow the acquisition of 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 folds of the eyelids are barely noticeable, the cartilaginous projection of the nose is very short and with holes facing upwards. The wrinkles located on the side of the mouth would adopt descending trajectories, while the upper lip would stand out due to its excessive thickness. With the passing of time, these features become more accentuated and aggravated.

Both the neurological and cardiac systems are severely compromised. The first case involves severe intellectual deficit, muscular atony, and tonic and clonic seizures ; while the second would precipitate significant malformations of the ventricular septum (25% of the time). At the skeletal level, substantial shortening of the extremities or reduced size of hands and feet, as well as deficient nail formation 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. This could be a deletion (a section of the chromosome disappears), or expressed as a translocation (the portion would not be lost but would join another chromosome other than the one it originally belonged to).

There is also what is known as inversion, in which the “piece” of chromosome remains in its original position but oriented in an opposite direction; or duplication, in which the same segment replicates itself on two occasions. 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 is a condition that severely affects both body and cognitive development. It is usually suspected from a marked delay in normal physical growth, which is accompanied by convulsions and the presentation of pathognomonic facial features.

The shape of the face has been named “Greek warrior’s helmet” . It is characterized by a flat and wide nasal bridge, with a short distance between the nose and the upper lip. The mouth projects downwards, 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 in the face. Only rarely is the cranial perimeter small (microcephaly), and there is evidence of altered tooth alignment or a cleft palate.

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

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

2. Cri du Chat syndrome (5p)

This chromosomal syndrome results from the deletion of genetic material located on the short arm of chromosome 5 . It is also sometimes labeled “Lejeune’s syndrome. The incidence is much higher in women than in men (3:1), and it is estimated that approximately one in every 20,000/50,000 newborns has it. It coexists with remarkable organic and cognitive co-morbidities, which limit autonomy or quality of life.

In the newborn it is common to show a tendency to acute crying (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 (breathing difficulty) and generalised jaundice (yellowish skin colour). Weight tends to be low at the time of delivery, when 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 particularities. The face is rounded and has flat cheeks, and there is also an epicanthal fold (covering the inside of the eyes, the part closest to the nasal septum). Both the jaw and the chin are not very prominent (micrognatia) 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 mouth leans significantly downwards.

The fingers and toes are shorter than usual. In addition, both show slight deformities, and gray hair often appears early in development. The presence of alterations in the heart can put your life at serious risk , and intellectual disability (normally of great intensity) limits independence in the 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 region 22q11.2, on chromosome 22 , which contributes to an embryo being able 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 4,000 new births and has many forms of expression, both physical and psychiatric.

The most relevant of these 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 present in a single or mixed form.

In terms of cognitive and psychological disorders, motor and learning difficulties, language acquisition delay (80%) and deficits in specific dimensions (working memory, speed of sensory information processing and abstract reasoning) stand out. Some disorders, such as those included in the category of anxiety, attention deficit and hyperactivity disorder and/or OCD (obsessive-compulsive disorder); 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 their lives.

4. Fragile X syndrome

Fragile X syndrome occurs after mutations in the FMR1 gene , which is intended to “instruct” 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 replicates 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).

Its face acquires particular features, with which its detection is possible: long and narrow face, big ears, prominent jaw and wide forehead. The feet are usually completely flat, without a bridge, and the toes are extraordinarily flexible . In a high percentage of cases, an endocrine based macro-orchidism (large testicles) is observed.

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

5. Robinow’s Syndrome

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

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In addition to the small size, short arms and legs are observed (especially in the former), which also extends to the fingers and toes (often fused by a syndactyly). The spine and ribcage are often disfigured, which causes intense pain and difficulties for correct motor skills .

At birth, the sexual organs often show substantial indifference, making the process of assigning a sex to the child difficult. Kidney/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 wide and prominent forehead and lips whose inverted V-shape can reveal the gums and upper teeth to the outside. The lower lip can also appear split, and it is characterized by alterations in the oral cavity such as ankyloglossia (union of the lower tongue with the base of the mouth). The teeth are presented in an irregular way, occupying the space reserved for the hard palate in many occasions. The eyes may be projected outward by malformation of the lower eyelid (false exophthalmos), which may 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 parental input or the presence of two genes exclusively from the mother. It generates a wide range of physical, mental and behavioural problems.

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

On a body level , poor muscle tone is also observed , with absolute atony when the child is suspended in the arms. Visual problems are common, especially myopia, and also congenital hypopigmentation (greyish colour in the eyes, hair and skin). Finally, the presence of scoliosis and small hands/feet, as well as defects in the genitals (both in the case of boys and girls) is noteworthy. On the face, it is often noticed that the eyes acquire an almond shape, and that the upper/lower lips lack volume. The head narrows where the temples are located, and the mouth projects noticeably downwards.

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

The most common behavioral problems involve irresistible outbursts of moodiness, tantrums and difficulty tolerating changes in the environment . Obsessive-compulsive habits, as well as anxiety and depression, may also be present, along with persistent scratching of the body .

7. Waadenburg syndrome

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

It is a syndrome that causes a whole succession of pigmentary anomalies (white tufts, pale eyebrows and eyelashes and light “spots” distributed on the surface of the skin). In many cases, heterochromia (different coloured eyes) can occur, as well as sensorineural deafness (usually bilateral) and a persistent obstruction of the intestine along with distension of the abdomen. Also usually occurs with anosmia (loss of the ability to smell) and malformations in the temporal bones of the skull .

8. William’s Syndrome

William’s syndrome, almost exclusively in girls, is the result of microblurring of chromosome 7. Many authors propose that there are two forms, one more severe than the other. It occurs in at least one in every 7500 births.

The face of those affected adopts a series of features that have earned them the nickname “goblin face” . In these cases you can see an elongated shape, with significant swelling in the periocular region (around the eyes). The forehead is broad and the nose is usually flattened, with a subtle chin and prominent lips. One of the most striking details, which is not always present, are the star-shaped irises (stars). 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. There can be heart failure (80%), lung involvement (80%) and endocrine disorders. Weight at birth is usually low, and it is not uncommon for excess calcium to occur during childhood. Digestive problems may be present throughout the life cycle, with a particular incidence of vomiting and recurrent constipation. Muscle tone is poor, contributing to joint deformities during the transition process from childhood to adolescence. By 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 above average . Despite this, spatial cognition tends to have deficient characteristics, and sleep disorders arise during childhood and adolescence (irregular pattern). A very high percentage (95%) develop hyperacusis, which results in 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.