What Is Noonan Syndrome?

Introduction 

Definition of noonan syndrome

While you might not have heard of Noonan Syndrome (NS) before now, it is a very common condition, affecting 1 in 1000 – 2500 people.¹ NS is a genetic disorder that is present at birth but may not be diagnosed until affected individuals are much older, depending on the severity (from mild to severe).¹ However, most cases are diagnosed in utero, at birth or in childhood. NS is also known as Ullrich-Noonan syndrome.²

NS is a syndrome, which means that the condition causes a range of symptoms which typically occur together. It has widespread effects, affecting almost all parts of the body, including the face, heart, lungs, brain, eyes, ears, kidneys, testicles (in boys), skin, blood, muscles, and bones, with the possibility of sometimes leading to serious complications if managed poorly.^1,2,3 The condition is characterised by unique facial features (facies), congenital heart defects, short stature, and varying degrees of developmental delays. Other characteristics include eye defects, blood clotting abnormalities, webbed/broad neck, undescended testes (cryptorchidism), sunken chest (pectus excavatum), pigeon/protruding chest (pectus carinatum), and scoliosis.^2,4,5 Unfortunately, as it is a genetic condition, there is no cure. However, NS can be managed symptomatically under proper medical supervision. 

NS was first characterised by Dr Jacqueline Noonan, an American paediatric cardiologist, in 1962 after she observed and treated 9 children with similar facial features and symptoms.² 

Causes and genetics 

NS is part of a group of conditions called RASopathies.³ These are conditions that are caused by abnormalities in the genes responsible for regulating the Ras pathway.³ The Ras pathway is needed to regulate the cell cycle and cellular differentiation, which in turn promotes normal growth and development in the body. Other conditions in this group include Costello syndrome, Legius syndrome, and Neurofibromatosis, amongst others.³ 

The gene most associated with NS is called PTPN11. A process called a missense mutation in PTPN11 leads to about 50% of all known NS cases.^1,2 Other affected genes include SOS1 (10-15% of cases), RAF1 and RIT1 genes (5% of cases). The remaining 30-35% of cases are caused by mutations in an assortment of other genes.²

Inheritance patterns and sporadic cases 

As mentioned, NS is caused by mutations in at least four genes: PTPN11, SOS1, RAF1, and RIT1. These mutated/faulty genes can either be passed from one of the child’s parents to the child (inherited) or the mutations in these genes can happen sporadically (without any known family history).^4,5

In situations where the faulty genes are inherited, this happens via an inheritance pattern known as autosomal dominant inheritance.^2,3 This occurs in 30-75% of cases.² Autosomal dominant inheritance means that only one parent needs to have the affected genes to pass them on, and each child has a 50% chance of having the condition.² The parents may or may not have features associated with NS. 

In contrast, in situations where NS occurs sporadically, neither parent is affected, therefore no faulty genes are inherited by the child. There is a very low likelihood that other children born to the same parents will have NS. Several poorly understood factors can lead to the condition happening sporadically. Due to how the affected genes are acquired, NS occurs equally in both people assigned male at birth (AMAB) and people assigned female at birth (AFAB), and prevalence is the same across all ethnicities.⁵ 

Symptoms of NS 

In this section, we’d explore the multiple effects of NS across the systems of the body and how the condition might present.

Facial features: the characteristic facies are one of the hallmark features of NS. Most, if not all affected individuals will have specific facial features. These include a wide forehead, widely spaced and drooping eyes (ptosis), pale blue or green eye colour, a flat nose with a wide base and bulging tip, a depressed groove in the centre of the upper lip, low set ears, a pointed chin (making the facial shape like an inverted triangle), and a broad/webbed neck.^3,5,6

Cardiovascular: about 50-80% of people with this condition have congenital heart defects.² This can require immediate treatment at birth or as the individual gets older. The different defects include:

• Pulmonary valve stenosis: this refers to the narrowing of the valve that regulates the flow of blood from the heart to the lungs. In severe cases, this can restrict blood flow from the heart to the lungs and lead to shortness of breath, chest pain, and even fainting. This is the most common congenital heart defect, affecting 25 - 71% of individuals with NS.⁴
• Hypertrophic cardiomyopathy: this refers to the thickening and enlargement of the heart, affecting its normal functioning. This defect affects about 10 - 29% of people with NS and typically presents within the first few months of life.²
• Other heart defects include narrowing of the mitral valve (which regulates blood flow between the left atrium and ventricle of the heart), holes in the heart (ventricular and atrial septal defects), patent ductus arteriosus and tetralogy of Fallot (which causes overriding aorta, narrowing of the pulmonary artery, ventricular septal defect and thickening and enlargement of the heart).^1,2

Growth: NS affects the growth hormone, causing most affected individuals to have short statures or statures at the lower end of normal.^2,4 However, at birth, people with NS usually have normal birth weights and lengths and start to experience slow growth in the first year of life, worsening in adolescence.¹ Babies with NS usually struggle to feed and fail to thrive. 

Skeletal features: NS can affect the chest wall causing about 28 - 95% of individuals to have sunken chests (pectus excavatum), and protruding chests (pectus carinatum).² NS can affect the spine, causing thoracic scoliosis and defects within the vertebrae. This condition can also lead to upper limb malformations, maxillofacial abnormalities like high arched palate and dental crowding, and reduced bone density and strength.^4,5

Developmental delay and intellectual disability: delayed psychomotor development is common in people with NS. Children with NS typically hit developmental milestones later than their peers without the conditions.^4,5 This could be due to a combination of factors like skeletal and joint abnormalities and visual and hearing impairments. Afterwards, most children will perform well in normal schools, but about 25% go on to have learning disabilities, requiring special education and persisting into adulthood.⁵ Studies have shown that about 23% of people with NS have IQs less than 70.^1,2 Language impairments and intellectual disability are common features of NS.²

Genitourinary: kidney problems are present in about 11% of people with NS but are usually mild.² The most common problem is the widening of the renal pelvis. Other kidney problems occur less commonly. 

NS can affect the reproductive system, delaying puberty in both people AFAB and people AMAB. However, typically they have normal fertility, but fertility in individuals, AMAB might be lower than normal.⁴ NS can also lead to undescended testes (cryptorchidism) in about 60-80% of people AMAB.^6,7 

Blood: NS can lead to blood clotting disorders like abnormal bleeding and bruising. In mild cases, individuals will have laboratory abnormalities in the blood cells with no clinical significance or mild bruising.⁶ In severe cases, individuals might bleed excessively requiring blood transfusion and clotting factors.²

Eyes and Ears: visual and hearing impairments of varying degrees are usually reported by several people with NS. Visual impairments include drooping eyes, strabismus, lazy eye (amblyopia) and double vision.^6,7 Hearing loss due to nerve damage or conditions like chronic otitis media is common.²

Skin: skin conditions like café au lait spots, lentigines and follicular keratoses might be seen in people with NS.²

Other features of NS include accumulation of excess fluid in the limbs and organs and breathing issues like laryngomalacia.⁷

Diagnosis 

Doctors can diagnose NS after taking a comprehensive history and conducting a physical exam of all the body systems. This is to look for characteristic features that would confirm the presence of this condition. For most people, this typically occurs at birth or in childhood.^1,2

Clinical evaluation and exploration of an individual’s medical history is the mainstay of diagnosing NS, however in situations where the diagnosis is not clear and other differentials are strong possibilities, some other methods can be used.^5,6 These include:

• Blood tests like Full blood count (FBC);
• Echocardiogram to detect congenital heart defects;
• Imaging tests like chest X-ray and CT scans;
• Genetic Testing: Specific genes are tested to confirm the presence or absence of mutations. This can help with the diagnosis of NS and rule out other conditions; 
• Other tests like high-resolution ultrasound can be used in pregnancies with 50% or more risk of NS.2 Babies can be tested in utero for prenatal features which may confirm NS diagnosis, including excess amniotic fluid (polyhydramnios), cardiac defects, fluid in the lungs (pleural effusion), obstruction around the kidneys (hydronephrosis) and increased nuchal translucency.^3,5 However, these features could be indicative of other conditions. 

Complications 

There are some significant risks associated with NS. These include:

• An increased risk of juvenile myelomonocytic leukaemia (JMML) and certain types of cancer. Children with NS are 8 times more likely to develop childhood cancers.^1,2 At age 20, the overall risk is about 4%²:
  • Increased risk of autism spectrum disorder ²
  • Increased risk of Noonan-like/multiple giant cell lesion syndrome ²

Treatment 

As mentioned at the beginning of the article, there is no cure for NS. However, symptomatic treatment can be provided under the guidance of qualified healthcare practitioners. Treatment can include:

• Devices such as glasses and hearing aids to help improve visual and hearing impairments 
• Medications to manage the effects of heart defects
• Medications to help the blood clot properly (medical advice might also be given to avoid anti-platelets like aspirin)
• Growth hormone therapy to increase growth rate
• Speech and language therapy for speech defects
• Special education to help with intellectual disabilities
• In some cases, surgery might be indicated to correct congenital heart defects, undescended testes and visual defects⁷

In all cases, a multidisciplinary team of specialists, including paediatricians, geneticists, cardiologists, and endocrinologists, is needed to manage patients with NS properly. Early detection of this condition is important to receive appropriate and timely care and improve prognosis. If managed appropriately, most individuals with NS will lead long and independent lives with appropriate support.

Summary 

In conclusion, Noonan syndrome is a genetic disorder characterized by a variety of physical and developmental abnormalities. It is caused by mutations in certain genes involved in the development and growth of various organ systems in the body. The syndrome is typically diagnosed based on clinical features, although genetic testing can confirm the presence of specific gene mutations.

While Noonan syndrome can have significant impacts on an individual's health and quality of life, early detection and intervention can help manage and minimize the associated challenges. Ongoing research aims to improve our understanding of the condition, develop more targeted treatments, and enhance the quality of life for individuals with Noonan syndrome.