He Noonan syndrome (NS) is a disorder of genetic type since it is transmitted from parents to offspring, being monogenic inherited autosomal dominant. This means that, with only one parent containing the affected gene, the child can develop the disease. (Atilano, Santomé, Galbis, 2013).
Thanks to the recent advances, the genes implicated in this disease and others comorbid have been discovered. The latest research labels Noonan Syndrome as a subtype within a broad spectrum of diseases called the"family of neuro-cardio-facial-cutaneous syndromes." Neurofibromatosis type 1, cardiofaciocutaneous syndrome or Costello syndrome, among others, are also included in this category.
Jacqueline Noonan was a pediatric cardiologist who investigated a number of patients with congenital heart disease.
In 1963, he published"Associated non-cardiac malformations in children with congenital heart disease,"describing in detail a group of children with a characteristic facial phenotype, short stature and malformations in the rib cage, and heart problems. These children suffered what would later be called s Noonan syndrome .
However, he was first called"Turner of the Men"thinking that it was the Turner's Syndrome , Until it was discovered that this last one arose by alterations in the sexual chromosomes.
A student of Jacqueline Noonan, Dr. John Opitz, began using the term"Noonan Syndrome"when he detected in children the same features that Noonan had described earlier in his work.
So, in 1971, this name began to be recognized officially. Scientists gradually became aware of the differences between this disorder and other partners, and different diagnoses were made.
Already in the 90's was when an area of the genome was detected that seemed to influence the origin of the Noonan Syndrome, which facilitated its differentiation as a disorder independent of other conditions with which it was confused.
Thanks to several studies, markers were discovered in an area of chromosome 12 called NS1, and later it was verified that this disease is genetically heterogeneous (Atilano, Santomé, Galbis, 2013). Little by little, more genes involved and their products were defined, which are linked to the signs and symptoms that we are going to describe here.
Prevalence
Approximately it is known that it appears between 1 of 1000 or of 2,500 live births worldwide. It affects both sexes equally (McGovern, 2015).
According to Ballesta-Martínez (2010), the proportion of cases of Noonan Syndrome is not yet known, however, family cases between 30 and 75% have been documented. In the latter, transmission is mainly maternal whereas the mutation of the allele transmission is usually by the father.
Causes
The mechanism that explains the onset of this syndrome is not yet fully understood. It appears to be associated with mutations in the signal transduction pathways of the RAS, MEK, RAF and ERK genes; Which play an essential role in cell proliferation.
Fifty percent of the patients also have mutations in the PTPN11 gene, while 13% have them in the SOS1 gene, and between 5 and 17% of the cases appear in the RAF1 gene. Less commonly, mutations have also been detected in the NRAS, KRAS, BRAF and MAP2K1 genes (McGovern, 2015).
Manifestations
The way in which it is expressed can be very variable (Ballesta-Martínez, 2010). Noonan syndrome begins to manifest itself from birth, although age influences the facial phenotype. So it is more evident in childhood and softens again when it reaches adulthood (McGovern, 2015).
- Low size (existing in approximately 80% of patients), becoming more noticeable in adolescence.
- Congenital heart disease: appear in 80% of patients. It is related to thoracic deformity, pulmonary valvular stenosis and hypertrophic cardiomyopathy among other conditions.
- Regarding the neurological aspects, can be found in these patients: Convulsive disorders , Hypotonia or Peripheral neuropathy .
- In some cases (about 25%) may appear intellectual deficit. Although they are usually slightly below average, with a score of CI Of 86.1 (the average is between 90 and 110 points).
- Psychomotor retardation.
- Craniofacial dysmorphism, as can be Hypertelorism (Excessive separation of the eye sockets) and elevated nasal bridge.
- Eyelid fissures sloping downwards.
- Problems of articulation of the language: influenced by the morphology of the palate (ojival palate), dental problems and poor control of the language.
- Short and pleated neck.
- Strabismus and errors of refraction (visual problems caused by the alterations in the form of the eyes of this syndrome).
- Amblyopia or vagus eye.
- Abnormalities in the outer ear, which may include ears of low implantation, rotated auditory pavilions, protruding ears or thick helix.
- Skeletal disorders (Ballesta Martínez, 2010). Being able to present scoliosis or thorax on the keel, which is likely to cause the individual's lungs and heart to malfunction and fatigue more easily.
- The Hyperlaxity Of the joints, being present in more than 50% of those affected.
- Hemorrhagic diathesis or greater ease of bleeding. It is present in approximately 55% of those affected. There may also be alterations in coagulation and platelet function (Ballesta-Martínez, 2010).
- In 25% of patients, it can be Hepatosplenomegaly (Enlarged spleen and liver).
- Genitourinary affections: as cryptorchidism in men, which means that the testicles do not descend completely throughout the development. Approximately 10% of the patients can have alterations in the kidneys.
- Skin problems: like Lymphedema , In which the skin appears inflamed or folded as a result of an accumulation of lymph within the subcutaneous tissue. They also present, in 67%, outstanding pads on the fingers and toes; Or follicular keratosis (rough skin) by 14%. You can also observe nevus, lentiges or stains"coffee with milk".
- Niemczyk et al proposed in 2015 that a significant proportion of children with Noonan syndrome had urinary incontinence during the day (36.4%), nocturnal enuresis (27.3%) and fecal incontinence (11.1%). Something that seems to disappear when puberty comes.
How is it detected?
A fundamental early sign is the size of the baby at birth, since they are usually somewhat smaller than the average. As we will see later, the weight may be higher in some occasions by accompaniment of lymphatic dysplasia (Ballesta-Martínez, 2010).
First, those affected by this syndrome should undergo a comprehensive assessment to delineate the existence and / or aspects of the disease. A detailed neurological, physical and genetic examination is imperative. The following tests are advised:
- Careful family history: Exploring if there were other previous cases of congenital heart disease, short stature, unusual facial features or mental retardation in parents or siblings of the affected.
- Evaluation of the level of development: Identify if there are delays. It is useful to pass a test that examines the Intellectual Quotient (CI).
- X-rays of the chest and back .
- Cardiac evaluation with electrocardiography and echocardiography: It is important to consult a cardiologist if the syndrome is suspected.
- Ophthalmologic and audiological tests .
- Renal ultrasound .
- Magnetic resonance Of the brain and cervicals if there are neurological symptoms.
- Blood Coagulation Panel .
- One way to confirm the diagnosis can be by DNA test Of the known causative genes.
It should be noted that it should not be confused with: Costello Syndrome , Turner's Syndrome , LEOPARD , Fetal Alcohol Syndrome , Williams syndrome Or stunted growth (McGovern, 2015).
Complications
- In the prenatal stage, the usual thing is that there are no complications. However, in some cases more severe polyhydramnios may appear (lack of absorption by the fetus of amniotic fluid, remaining too much of this); Fetal edema, cystic hygroma (tumor that is born in the head or neck) or pulmonary valvular dysplasia.
- Small increase in the risk of developing cancer, since there are mutations in the RAS gene and in PTPN11 that are associated with both the Noonan syndrome and the appearance of certain types of cancer.
- Likelihood of developing myeloproliferative disorder and myelomonocytic leukemia.
The first cause of mortality of this disease depends on the existence and type of congenital vascular diseases.
- It can be associated with low self-esteem or depression (Ballesta-Martínez, 2010).
Treatment
Treatment of Noonan Syndrome will depend on the symptoms presented and their severity. The intervention is focused mainly on:
- Treatment of the heart: It is important that the cardiac function is examined periodically. Effective drugs are usually used to alleviate heart problems. If the involvement involves the valves of the heart, surgery may be appropriate.
- Treatment for delayed growth or psychomotor problems: In many cases, levels of growth hormone Are below normal, so that growth hormone therapy with somatropin (Norditropin) has been shown to be effective.
Roman at al. (1996) studied the growth hormone response in children with this syndrome for about 4 years, noting that there is a significant improvement in height, even half of the participants in adulthood exceed the expected height.
At first it was thought to improve only in cases of patients without mutation in PTPN11, but the evidence shows that its long-term use is beneficial in all patients.
- Adequate food: As this syndrome often causes problems in the individual's diet. In the newborn, it may be necessary to have a nasogastric tube or gastrostomy.
- Address learning difficulties: With personalized educational programs adapted to the child. If it is detected from an early age, it is essential to stimulate it by establishing an enriched environment for it.
- Intervention at the hearing: It is important to have exams at least every two years, since it is common to have vision problems in this condition. In some cases, such as cataracts, surgery may be needed.
- Treating abnormal bleeding: For this, acetylsalicylic acid (aspirin) and products containing it should be avoided. Depending on the conditions of each person, the doctor may prescribe medications to regulate blood clotting.
- Improve lymphatic problems: Although the symptom is not so common, it is necessary to take it into account since, having different causes in each affected, it can be difficult to establish a correct treatment.
In the case where fluid collects around the lungs and heart, it may be necessary to introduce a tube into the chest to drain the fluid. If the problem persists, surgery should be used.
- To solve alterations in the genital and urinary tract: If the problem is about testicles that have not gone down, surgery will probably be advised. This option is recommended before the child starts school.
If it is a urinary tract infection, your doctor will prescribe the necessary antibiotics. In contrast, if we talk about testicular malfunction, testosterone replacement can be used.
There are currently many organizations and associations that offer support to those affected and families with Noonan Syndrome, such as the Spanish Association Noonan Syndrome, the Civil Association Noonan Syndrome of Argentina or Association of Noonan Syndrome in Cantabria, to mention just a few.
Prevention
As this disease is genetic, prevention is focused on this aspect. There are cases where mutations occur for the first time (new cases), however, they cover less than 1% and it is not yet known exactly what triggers them.
The affected patient will have a 50% risk in each pregnancy of transmitting this disorder to their offspring, so the person must know this information when he is considering forming a family. If the molecular defect has been detected, a prenatal genetic study can be performed in future pregnancies.
The essential thing is to detect the symptoms as soon as possible, especially if there is already a family history of this syndrome.
References
- Ballesta-Martínez, M.J. And Guillén-Navarro E. (2010). Noonan syndrome. Protoc diagn pediatr. 1: 56-63.
- Carcavilla, A., Santomé, L. and Ezquieta B. (2013). FROM THE CLINIC TO THE GEN, OR FROM THE GEN TO THE CLINIC? Noonan syndrome. Rev Esp Endocrinol Pediatr 4: 71-85.
- Niemczyk, J., Equit, M., Borggrefe-Moussavian, S., Curfs, L., von Gontard, A. (2015). Incontinence in persons with Noonan Syndrome. J Pediatr Urol 11 (4): 201. E1-5.
- Noonan, J.A. (1968). 116 (4): 373-80. "Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease". Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Noonan. J.A. Am J Dis Child. Oct;
- Noonan syndrome - Treatment. (8 July 2015). Retrieved June 6, 2016, from NHS Choices.
- Romano, A.A., Blethen, S.L., Dana, K. & Noto R.A. (nineteen ninety six). Growth hormone treatment in Noonan syndrome: The National Cooperative Growth Study experience. The Journal of Pediatrics, 128 (5): S18-S21.
- Wikipedia. (S.f.). Retrieved on June 6, 2016, from Noonan Syndrome.