- 1 Definition
- 2 Epidemiology / Pathological Process
- 3 Clinical Presentation
- 4 Diagnostic Procedures
- 5 Differential Diagnosis
- 6 Similarities and Differences between NS and Other Disorders
- 7 Management / Interventions
- 8 Other names for this condition
- 9 Prevention
- 10 Prognosis
- 11 References
Noonan Syndrome (NS) is an autosomal dominant condition or a genetic mutation that prevents the normal development of different parts of the body.  It is a genetic condition that affects both girls and boys in so many ways including:
- Distinctive facial features such as the broad or webbed neck, drooping eyelids, and a wider-than-usual distance between the eyes
- Health problems such as short stature
- Chest deformity
- Congenital heart disease
- Pulmonary stenosis
- Physical problems
- Possible developmental delays
Noonan and Ehmke were the first to describe a succession of patients with the same similarities including unusual facies and multiple malformations like congenital heart disease. As a result, these patients were previously thought to have a form of Turner Syndrome, which has a lot of similarities in its clinical features with Noonan Syndrome.
The eponym “Noonan syndrome” was then adopted in recognition of Dr. Jacqueline Noonan who was the first to indicate that this condition occurs in both genders; could be associated with normal chromosomes included congenital heart defects and could be familial.
Epidemiology / Pathological Process
The Noonan Syndrome is caused by a mutation of a gene or a damaged gene that is usually inherited from one of the parents. The most commonly altered genes are:
- The PTPN11 gene
- The SOS1 gene
- The RIT1 gene
- The KRAS gene
Even though the symptoms are usually the same for all different genes, two of them are associated with specific conditions. The faulty PTPN11 gene is commonly associated with pulmonary stenosis and the faulty RAF1 gene, associated with cardiomyopathy.
NS can be caused by mutations in multiple genes that occur at different degrees. The majority of people with NS (50%) have mutations in the PTPN11 gene. Mutations in the SOS1 gene are found in 10 to 15% of cases whereas mutations in the RAF1 and RIT1 genes occur in 5% of cases for each of them. Mutations in other genes each account for a small number of cases.  Additionally, approximately 2% of people with NS have mutations in the KRAS gene and have a more severe or atypical form of the condition. The cause of NS in 15 to 20 % of people with this disorder is unknown. No matter how they acquired the gene mutation, people with Noonan syndrome have a 50% (1 in 2) chance of passing it onto their children.
There are 2 types of mutations that cause Noonan Syndrome:
- Inherited: Children who have one parent with NS who carries the defective gene (autosomal dominant) have a 50% chance of developing the disorder.
- Random: NS can develop because of a new mutation in children who don't have a genetic predisposition for the disorder (de novo).
The condition is present from before birth, although milder cases may not be diagnosed until a child gets older. Its incidence is believed to be between 1 in 1000 and 1 in 2500 children.
NS is most often characterized by facial and musculoskeletal features. Although these features are more present during early childhood, they change over time and appear less characteristic during adulthood:
- In the newborn infant, the head is large with a small face, a tall forehead, wide-spaced eyes, short nose, low set ears, and a broad or webbed neck
Many infants with NS also have heart (cardiac) defects such as
- Pulmonary valvular stenosis
- Hypertrophic cardiomyopathy
- Septal defects
The following characteristics are also seen among individuals with NS:
- Short stature: up to 83% of people with NS have a short stature
- Pectus deformity of the chest with pectus carinatum (protrusion of sternum and rib) and pectus excavatum (hollow chest)
- Cubitus valgus (outward deviation of the elbows)
- Rounded shoulders
- Rib abnormalities
- Genu valgum ( Knock knees)
- Joint hyperextensibility
- Talipes equinovarus
Individuals with NS may also present less common problems including:
- Learning disability: children with NS tend to often have a mild learning disability due to a lower IQ average
- Feeding problems: children with NS may have problems with sucking and chewing
- Speech problems: articulation difficulty due to a high arched palate and weak muscles
- Behavioral problems: some children with NS may have attention problems or difficulty to describe their or people emotions
- Eyes condition such as squint, lazy eye
- Hearing loss
- Hypotonia: decreased muscle tone will make children with NS reach early milestones later compared to other children
- Undescended testicles: one or both testicles may fail to drop into the scrotum in boys with NS
- Infertility can be diagnosed in boys if undescended testicles are not corrected at an early age
- Bone marrow problems- Leukemia
- Skin problems such as dystrophic nails; extra prominence on pads of fingers and toes; follicular keratosis; hyperelastic skin; moles; thick curly hair or thin sparse hair.
NS may be suspected before birth based on the results of fetal ultrasonography. The diagnosis of Noonan syndrome can be made clinically by observing the specific characteristics associated with the condition. These specific characteristics include congenital heart defect; a developmental delay that may vary depending on people; short stature; chest malformations as well as facial features. However, because these symptoms can have different causes, further testing is suggested to determine the extent of the symptoms. They may include:
- Genetic Testing
- Electrocardiogram (ECG)
- Blood Tests
- Educational Assessment
- Eye Test
- Hearing Test.
- Plotting of growth parameters on NS growth charts
- Renal ultrasound examination
- Clinical and radiographic assessment of the spine and rib cage
- Brain and cervical spine MRI if neurologic symptoms are present
- Multidisciplinary developmental evaluation.
Several conditions identified as RASopathies have similarities with NS. These conditions all have similar signs and symptoms and are caused by changes in the same cell signaling pathway. Besides NS, the RASopathies consist of cardiofaciocutaneous syndrome, Costello syndrome, Neurofibromatosis type 1, Legius syndrome, and Noonan syndrome with multiple lentigines. The differential diagnosis, therefore, includes Williams syndrome, intrauterine exposure to primidone, fetal alcohol syndrome, and Aarskog syndrome. Other cardiocutaneous syndromes such as LEOPARD syndrome, Neurofibromatosis, and Watson syndrome have a markedly overlapping phenotype.
Similarities and Differences between NS and Other Disorders
|TURNER SYNDROME||Girls with NS and Turner Syndrome can have:
|FETAL ALCOHOL SYNDROME||
|MOSAIC TRISOMY 22||
||No congenital heart defects are seen
Cognitive development more impaired
|AARSKOG SYNDROME ( faciogenital dysplasia)||
Management / Interventions
Although it's possible to treat many aspects of NS, there is no typical treatment of NS. Because the presentation of NS can be mild and the typical facial features lessen with age, the diagnosis might be neglected or missed. Therefore, a regular comprehensive follow-up in a multidisciplinary approach is needed to manage the medical and developmental complications of Noonan syndrome.
The medical treatment will focus on problems such as:
- Heart Defects:
- With pulmonary stenosis: no treatment will be required if it's mild. If it's severe a surgery to narrow the valves will be required
- Hypertrophic cardiomyopathy may need to be treated with either medication such as beta-blockers or surgery to remove or destroy some of the excess heart muscle
- Septal defects usually get better with age and thus do not need any treatment.
- Growth issues: A growth hormone therapy is given around 4 to 5 years old. The medication Somatropin, a single daily injection is the most used. By adulthood, some people with NS may have normal height, but short stature is more common.
- Feeding and speech problems: Speech Therapy is needed to effectively use the muscles of the mouth and develop them.
- Undescended testicles: A surgical procedure called orchidopexy is performed
- Learning Disabilities: Special educational needs and the assessment procedure.
- Gross and fine motor delays to be assessed and treated by Occupational Therapists and Physiotherapy
People of any age with Noonan syndrome may be at an increased risk of cancer. They need to adopt healthy habits throughout life. It is imperative that they regularly do have physical checkups and screenings.
In addition to medical management, patients may need to be referred for physiotherapy. The physiotherapy treatment will focus on patient education, improvement of the range of motion; strengthening exercises as well as pain management.
Early Intervention is crucial for a child diagnosed with Noonan Syndrome as they have delayed motor milestones. The following exercises improve and maintain flexibility, endurance, strength, coordination, and balance in children with NS:
- Sit-ups: From lying down on their back the child comes up to a full sitting position by holding the therapist's fingers
- Tall kneel: This is a great exercise for balance and core strength
- Sitting balance as a great activity for core balance, strength, and body awareness.
- Sit to stand from step stool: This is a great leg strengthening activity as the child stands up from the sitting position.
- Stepping over obstacles: it's an important activity as balance is challenging for children with NS
- Crawling over pillows as a great overall strengthening and motor planning activity.
- Stair negotiation skills: As children with NS have a hard time alternating their feet on the stairs because of poor balance and short stature; this is a very good practice for them.
- Therapy ball: The child lies on their back over the ball and reaches back for something, and comes up to a sitting position
- Passive bicycle kicks while singing
- Standing or walking on different surfaces such as hardwood floor, pillows, balance disc, shoes on grass, shoes on wood chips at the playground.
- Lying on the back to massage the bottom of their feet for proprioceptive input; which helps with independent walking and balance on the stairs.
- Joint Compressions help in body awareness with independent standing/walking and balance on various surfaces.
In their study on perceived motor problems in daily life, Croonen et.al (2016); showed that people with NS reported particular problems related to pain; decreased muscle strength, fatigue, and clumsiness and their evident impact on functioning in their daily activities. Most people with NS believed that exercise, appropriate physiotherapy advice, and other supportive intervention are key elements to improved motor performance.
Other names for this condition
- Familial Turner syndrome female pseudo-Turner syndrome
- Male Turner syndrome
- Noonan-Ehmke syndrome
- Pseudo-Ullrich-Turner syndrome
- Turner-like syndrome
- Turner phenotype with normal karyotype
- Turner syndrome in females with X chromosome
- Ullrich-Noonan syndrome.
There is no known way to prevent Noonan Syndrome because it occurs spontaneously, However, it is recommended that people with a history of NS get genetic counseling before they have children. If Noonan syndrome is detected early, it's possible that ongoing and comprehensive care may lessen some of its complications such as heart disease.
Noonan Syndrome is a lifelong condition. People with NS are differently affected and therefore their life expectancy will depend on the presence and severity of congenital heart defects Noonan Syndrome. Available from:
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