Noonan syndrome is a rare, sometimes hereditary, genetic disorder that alters the normal development of different anatomical parts of the body. Unusual facial features, short stature and some congenital heart defects are the main pathological and diagnostic signs.
The consequences of the pathology are not always dramatic: in some cases, in fact, the Noonan syndrome can cause a nuanced symptomatology and allow a normal life.
Brief reminder of genetics: DNA and chromosomes
Before describing Noonan syndrome, it is good to make a brief reference to genetics.
CHROMOSOMES AND DNA
Every cell of a healthy human being has 23 pairs of homologous chromosomes : 23 are maternal, that is, inherited from the mother, and 23 are paternal, or inherited from the father. A pair of these chromosomes is sexual, that is, it determines the sex of the individual; the remaining 22 pairs, instead, are composed of autosomal chromosomes . In their entirety, the 46 human chromosomes contain the entire genetic material, better known as DNA . In the DNA of an individual are written his somatic traits, his predispositions, his physical abilities etc.
GENES AND MUTATIONS OF DNA
DNA is organized in many sequences, more or less long, called genes . Each gene occupies a specific chromosome and its counterpart, as it is present in two copies, called alleles . An allele comes from the mother and resides in the maternal chromosome; the other allele comes from the father and is housed in the paternal chromosome.
Figure: the organization of a gene within a pair of homologous chromosomes. A pair of homologous chromosomes contains specific genes, all having two variants, the alleles, occupying the same chromosomal position and doing the same functions (except mutations). The left pair of chromosomes has two equal alleles (both blue); the right pair instead has two different alleles (one is red, the other is blue).
From the genes the proteins originate, present in our body. When a DNA mutation occurs, a gene (usually an allele) of a given chromosome can be defective and therefore produce a defective protein.
What is Noonan syndrome
Noonan syndrome is a genetic, sometimes hereditary disease that causes several anatomical anomalies (and not only) in several parts of the body. The main changes occur in the face, heart and skeletal system, but it is possible that the reproductive system, the lymphatic system, the skin, the nervous system, the eyes, the ears, the blood and the kidneys.
The abnormalities that characterize Noonan syndrome are not always the same in all patients: in some they are blurred, so much so that they pass almost unnoticed and allow for an almost normal life; in someone else, on the other hand, they are so accentuated as to endanger those who wear them.
Noonan syndrome is uncommon: in fact, it affects one child every 2, 500 newborns. Males and females are equally affected and there is not one ethnicity in particular more predisposed than others.
Noonan syndrome is a genetic disease, therefore it is caused by a change in DNA . The researchers are pretty sure that at least eight genes are involved, yet they still can't clearly explain how they cause anatomical abnormalities.
What do these eight genes do?
The genes involved in Noonan syndrome have a particular physiological role: they produce proteins that allow the growth and development of our cells. In other words, these proteins are regulatory ends, which take care of the life and destiny of every single cell in great detail.
When the genes that create these proteins mutate, the cellular regulation mechanisms described above are also altered, with serious damage to the body.
THE GENES INVOLVED
Of the eight genes implicated in Noonan syndrome, only four have been fully identified, as they change with a statistically appreciable frequency.
- PTPN11 : its mutation characterizes around 50% of cases. It resides on chromosome 12 and the discovery of its implication in Noonan syndrome dates back to 2001. The protein, which it produces, has a fundamental role during embryonic development: it governs, in fact, the growth, differentiation and division of cells, those of the heart in particular. We know for sure that a mutated allele is enough for the disease to appear (dominance).
- SOS1 : mutated in 10-15% of cases. It was understood that he could be involved in the disease in 2006.
- RAF1 : mutated in 5-10% of cases. His role was not known until 2007.
- KRAS : its mutation characterizes about 2% of cases. The discovery of its implication is recent: 2006.
As you can see, the research related to these genes is quite recent and this explains why they are still pending.
INHERITANCE ?: YES OR NOT?
Genetic mutations, in 50% of cases, are sporadic (ie due to randomness), while in the remaining 50% they are transmitted by one of the parents .
Usually, those parents who transmit the disease to their children do not know that they are affected by Noonan syndrome, as this is probably not a serious and obvious form.
Noonan syndrome manifests itself with several characteristic signs in several parts of the body.
These signs consist of more or less pronounced anatomical anomalies and in more or less serious pathological conditions. In fact, some patients manifest the disease clearly, in every respect; others, on the other hand, are more nuanced or limited to some sites.
MAIN AND SECONDARY PATHOLOGICAL CHARACTERISTICS
Unusual facial features, short stature and a series of congenital heart defects are the abnormalities found in all those who suffer from Noonan syndrome; for this reason, the main characteristics of the disease are considered (NB: the congenital term means present from birth ).
Instead, the following anomalies are considered secondary characteristics, as they are less common than the previous ones:
- Easy appearance of hematomas and hemorrhages
- Learning difficulties and behavioral anomalies
- Visual deficiencies of various kinds
- Muscular hypotonia
- Hearing loss
- Infertility and abnormal genital apparatus
- Difficult feeding (in childhood)
- Skeletal anomalies
THE TREATMENTS OF THE FACE
The abnormal facial features can be noticed already when the patient is very small; over time, then, their variation is observed, becoming permanent in adulthood.
- Very early infancy (less than a year): the eyes are distant from each other and tend towards the bottom. The ears are low and oriented towards the back of the head. The groove, present above the upper lip, is deep; the neck is short and the hairline behind the head is low.
- Childhood : the eyes begin to become prominent, while the eyelids are lowered ( ptosis ) and become thicker. The nose is crushed at the root, but has a broad base and a bulbous tip.
- Childhood : the previous characteristics are added an inexpressiveness of the face, enlarged lips and a greater length of the face.
- Adolescence : the forehead becomes wide and the chin is pointed, thus making the face similar to a triangle. Some facial features are accentuated, such as the lines that start from the nose and reach the corners of the mouth, while the eyes become less prominent. The short neck is enriched with other details: the first folds ( pterigium colli ) appear and the trapezius muscles are more voluminous.
- Adult age : the furrows that run from the nose to the sides of the mouth are deep and evident. The mouth becomes even more prominent and the skin becomes wrinkled and clear. The eyes are always distant and with the eyelids thickened and affected by ptosis.
Weight and length at birth are normal. However, in the first 18-24 months, growth is observed to be slow and delayed compared to children of the same age.
Figure: the face of an adult with Noonan syndrome. From the site: login.aafp.org
This is due to a hormonal issue ( growth hormone, GH ), but also to some difficulties, which the child has in eating.
Growth retardation is also observed during childhood and, above all, during puberty, when boys tend to develop suddenly. Differences from peers at this time in life are obvious.
In the absence of treatment, the height in males reaches an average of 162 cm, while in females it reaches 153 cm. With the right therapeutic treatments, the height can also fall within the normal average.
CONGENITAL CARDIAC DEFECTS
80% of patients with Noonan syndrome are born with more or less serious heart defects. These anomalies can be:
- Stenosis of the pulmonary valve : this is a narrowing (stenosis) of the heart valve (which allows the blood to flow from the right ventricle of the heart towards the pulmonary artery). The pulmonary artery is responsible for transporting blood to the lungs due to its oxygenation.
- Stenosis of the pulmonary artery : it is a narrowing of the pulmonary artery; this defect, like the previous one, limits the amount of blood reaching the lungs for oxygenation.
Figure: one of the cardiac defects typical of Noonan syndrome: the stenosis of the pulmonary valve. From the site: hinsdale86.org Hypertrophic cardiomyopathy : it is an abnormal growth and thickening of the myocardium, or the heart muscle. This condition alters cardiac function.
- Defect of the inter-ventricular septum (between the ventricles) or inter-atrial (between the atria): consists in the formation of a hole between the wall of tissue that separates the ventricles (or that which separates the atria). This causes the blood to flow between the two compartments, causing circulatory problems, sometimes even serious ones.
As these are numerous events, we will try to describe them in their main features.
- Learning difficulties and behavioral anomalies . Intelligence can be lower than average. However, there are many individuals who, despite being carriers of the disease, have a normal IQ.
The same goes for behavior: in some cases, the patient is irritable, repeats the sounds and words of other people and has strange dietary requirements.
- Easy appearance of hematomas and hemorrhages . In 50% of patients, coagulation abilities are reduced. Therefore, blood loss, even after trivial trauma, is conspicuous. It is a characteristic not to be overlooked when taking certain drugs (aspirin) or undergoing surgery (all, from the most invasive to the simple extraction of a tooth).
- Visual deficiencies of various kinds . About half of the patients have vision problems of various kinds. Strabismus, astigmatism, myopia, lazy eye ( amblyopia ), hypermetropia and nystagmus are the possible visual defects that can arise in a patient with Noonan syndrome.
- Lymphedema . This is a defect in the lymphatic system . Lymphatic fluid, or lymph, accumulates in some areas of the body, such as the hands and feet. It occurs mainly during childhood.
- Muscular hypotonia . This is a reduction in muscle tone. It is typical of childhood and childhood.
- Hearing loss . This is a temporary episode during youth. It is due to frequent otitis of the middle ear.
- Infertility and abnormal genital apparatus . Genital disorders are observed in 60% of patients. Often, the subjects are males, who suffer from cryptorchidism (ie the failure of one or both testicles to descend into the scrotum). To solve this problem, surgery must be used. Otherwise, that is without the intervention, the individual has a reduced number of spermatozoa, therefore he is less fertile.
Women with Noonan syndrome usually do not have these problems.
- Difficult feeding . It is a typical problem of childhood and which contributes to delaying growth. The child has problems with breast milk suction and tends to vomit after every meal.
- Skeletal anomalies . Especially in young adolescents, articular hypermobility (ie joints with a wide range of motion), scoliosis, chest excavatum (or funnel), chest can be seen and nipples spaced apart in an unusual way.
WHEN AND FOR WHAT REASON DO I REFER TO A DOCTOR?
If you notice facial features such as those described above in a child, it is advisable to have the small patient undergo a pediatric examination. The doctor will then make the appropriate assessments and, if he suspects Noonan syndrome, will carry out the necessary diagnostic tests.
In some cases, the anatomical anomalies are blurred, so that those who are carriers of the disease do not know they are affected. However, even in these situations the diagnosis is important, due to the cardiac problems that could arise.
Complications related to Noonan syndrome depend on the degree of severity of the disease. Therefore, from this point of view, each patient represents a case in itself.
Among the main complications, they deserve a quote:
- Serious intellectual delay
- Extremely impaired blood coagulation capacity
- Lymphedema formation around vital organs, such as the heart and lungs
- Serious anatomical anomalies of the genital apparatus, with repercussions on the urinary one (in particular the kidneys)
A disease such as Noonan syndrome, characterized by a huge number of particular signs, can be diagnosed even after an objective examination . However, in some cases the disease is not very evident, so that, as has already been said on several occasions, it can go unnoticed until puberty or adulthood (when the patient's first sexual needs arise).
In any case, to clarify any doubts, there are very reliable genetic tests, such as the so-called karyotype .
Once the disease is diagnosed, it is important to monitor, through specific tests, the pathological conditions that are potentially dangerous for the patient, such as heart defects or reduced coagulation abilities. Depending on the outcome of these tests, the severity of each case considered can be accurately established.
The most important signs in the physical examination:
Monitoring is performed by:
Being a genetic disease, Noonan syndrome is not curable.
However, the symptomatology that it produces can be limited and alleviated through fairly effective therapies.
CARE OF HEART PROBLEMS
Knowing which are the disorders that afflict the heart is essential to be able to set the most appropriate therapy.
Certain cardiac anomalies can be controlled with a simple pharmacological treatment (diuretics, antiarrhythmics and beta-blockers); others more serious (for example the stenosis of the pulmonary valve or the defects of the septum) may require surgery.
In any case, periodic monitoring is essential, as a seemingly innocuous situation can turn into something very serious and dramatic developments.
HORMONAL CARE FOR GROWTH
Often, reduced statural development is due to poor growth hormone production, or GH . Therefore, the exogenous administration of one of its analogues ( somatropin ), created in the laboratory, has excellent effects, provided that the therapeutic program is scrupulously followed. The latter is very simple: daily injections, starting from 3-5 years of life.
Side effects are rare and consist mostly of itching and redness in the injection area.
Periodic monitoring of hormone levels is recommended.
CARE OF THE LEARNING DEFICIT
In some cases, Noonan syndrome can significantly impair intellectual faculties. In these situations, the patient needs valid support, especially at school.
For visual defects, glasses suitable for the diagnosed pathology may suffice; it is rare to have to resort to surgery.
As for the coagulation problems, there are drugs that promote coagulation, to be administered in time of need. Furthermore, a recommendation to remember is not to take anticoagulants, such as aspirin and its derivatives.
If lymphedema is formed around critical organs such as the heart or lungs, lymphatic fluid can be drained by inserting a special tube. Surgery, in these cases, is a rare possibility.
Finally, as regards infertility and genital defects, it is possible to resolve criptorchidism with a specific intervention (NB: the reader is reminded that infertility, in Noonan syndrome, is a typically male problem).
The prognosis varies from patient to patient. In some individuals, in fact, the Noonan syndrome causes a nuanced symptomatology and allows an almost normal life (provided that appropriate treatments are applied); in others, however, it seriously compromises intellectual capacity and general health.
Therefore, the prognosis can be positive (first case), but also negative (second case).
Alongside these two extreme situations, moderate cases are inserted, that is to say the middle ground between the non-serious shaded forms and the severe ones. Faced with these circumstances, for the prognosis to be positive, early diagnosis is essential followed by adequate and early treatment. Only then can the prognosis have a positive impact.
Unfortunately, preventing sporadic mutations is not possible. Hereditary forms, on the other hand, can be prevented by informing fertile individuals, suffering from Noonan syndrome, of the possibility of transmitting the disease to their children.