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Noonan Syndrome Factsheet by
Dr. Judith Allanson, M.D. Clinical Genetics

This pamphlet is intended to give the patient and his / her family an overview of Noonan Syndrome. A Syndrome is a pattern of signs and symptoms that collectively characterise a particular condition. Noonan Syndrome is a commonly encountered pattern which, in general, is recognized by the associated congenital heart disease and short stature. The physical appearance in Noonan Syndrome is distinctive, and it changes with age.

What follows is a short history of Noonan Syndrome and a description of the physical findings, inheritance and future outlook of this disorder. This brochure is an outline based on the experience of a large number of patients, their families and health professionals. Additional information can be supplemented by your physician.

In 1963, Dr. Jacqueline Noonan, a paediatric cardiologist at the University of Kentucky, recognized that an unusual congenital heart defect - valvular pulmonary stenosis - was sometimes accompanied by short stature and a characteristic physical appearance with a webbed neck, wide spaced eyes and lowset ears. Both males and females were described. The pattern was seen to occasionally run in families. Chromosome analysis was normal.

Confusion has arisen between what is now known as Noonan Syndrome and a separate condition described in 1938 by H.H. Turner. Turner Syndrome has some similar features, including neck webbing, and short stature. It only occurs in females and is caused by loss of a sex chromosome (an X or Y chromosome).

For many years these two disorders have been muddled. Careful clinical examination, chromosome analysis and recognition that Noonan Syndrome affects males and females, and can run in families, in multiple generations, serve to distinguish these two conditions.

Features associated with the eyes:
In 95% of newborns the eyes are widely spaced (hypertelorism) with the outer border of the eye slanting downward. Other commonly associated features are drooping of the eyelids (ptosis), an extra fold of skin at the inner corner of the eye (epicanthal fold), and diamond shaped eyebrows. Problems less frequently seen are crossed eyes (strabismus), near sightedness (myopia) and prominence of the eyes (proptosis). Many individuals with Noonan Syndrome have striking blue or blue/green eyes.

Features associated with the head and neck:
Over 90% of infants with Noonan Syndrome have backward rotated, low set ears with a thick fleshy outer border (helix). Over 90% have a prominently grooved upper lip (philtrum) and cupid's bow lips. The nose in Noonan Syndrome is small with an upturned tip. The roof of the mouth (palate) is often arched, with a small lower jaw (micrognathia). One of the most characteristic features in the newborn is excess neck (nuchal) skin with a low hair line at the nape of the neck.

The facial characteristics stated above change with age in a predictable way. In the newborn baby, the head appears to have a tall forehead and an oval or round face. In childhood, the face becomes more triangular (a broad forehead tapering to a pointed chin), with, sometimes, expressionless features. As the child reaches puberty and young adulthood, ptosis lessens and the features, in general, become much sharper. The neck lengthens with age, and may appear broad or webbed.

Features associated with the heart: Over two-thirds of patients with Noonan Syndrome have a congenital heart defect. The heart is a four chambered pump with two controlling outflow valves and two valves that control flow into the heart. The heart is divided into four chambers, two on the right side, and two on the left side. The two lower chambers or ventricles are the muscular pump. The deoxygenated blood (after the body has removed the oxygen) is returned via the veins to the right upper chamber or atrium. Blood flows from the right atrium past the first valve (tricuspid valve) into the right ventricle. The right ventricle then contracts and pushes the blood past the second valve (pulmonary valve) towards the lungs. The blood is oxygenated in the lungs then flows via the pulmonary arteries into the left atrium. From there, the blood flows past the third valve (mitral valve) into the left ventricle, which contracts and forces the blood past the fourth valve (aortic valve) into the arteries, providing oxygenated blood to the entire body, and brain.

Over 50% of patients have valvular pulmonary stenosis (narrowing of the pulmonary valve). Because this narrowing increases the work done by the right ventricle, its muscle increases in size (hypertrophies), and produces characteristic changes in the chest x-ray and electrocardiogram. Of the remaining cardiac defects, approximately 10% are atrial septal defects (a hole in the wall dividing the right and left upper chambers) and another 10% are ventricular septal hypertrophy (an increase in the size of the wall dividing the right and left lower chambers). Ventricular septal defects (a hole between the right and left lower chambers) are also found. Many cardiac anomalies associated with Noonan Syndrome are minor and need only annual follow up by a physician.

However, some heart lesions need surgical repair to increase cardiac efficiency.

Features associated with the skeletal system and growth:
Birth weight is generally average but may be slightly high due to accumulation of fluid in the tissues (edema). 40% of infants with Noonan Syndrome gain weight poorly and fail to thrive during the first years of life. The average birth length in Noonan Syndrome is 47cm (3-5cm less than the average). Childhood growth patterns tend to be at the lower limit of the normal range. The characteristic pubertal growth spurt may be absent or reduced. Adults with Noonan Syndrome are usually, but not always, short in stature (males 5'3" - females 4'11"). Normal growth curves are now available for males and females with Noonan Syndrome. Detailed evaluation of the cause of growth delay has rarely been performed. The possibility of growth hormone deficiency is now being looked into. It has not been found to date.

In Noonan Syndrome there is a characteristic breast-bone (sternum) deformity with a funnel chest (pectus excavatum) below and a pigeon chest (pectus carinatum) above. The chest often has widely spaced nipples. Shoulders are commonly rounded or slouched. Finger tips are blunt and squared.

Features associated with the skin and teeth:
The hair is frequently curly or woolly.

There are a number of skin features that have been mentioned in Noonan Syndrome, including birth marks (pigmented nevi) varying in colour from light yellow to black, and coffee coloured (cafe-au-iait) spots. A third of patients have dental malocclusion with an increased potential for cavities.

Features associated with the blood system (Haematology):
Almost one in five individuals with Noonan Syndrome has a mild bleeding abnormality. This may show itself as easy bruising, persistent oozing from wounds or nose bleeds (epistaxis). It is important to evaluate the child or adult with Noonan Syndrome for clotting problems, especially prior to surgery, as in general they are easily treated.

Features associated with the Genitourinary system:
Most males, at birth, have undescended testicles (cryptorchidism). Without treatment this may lead to delayed puberty and/or reduced fertility. The majority of females have normal puberty and are fertile.

Features associated with the learning intelligence and behaviour:
Intelligence is variable in Noonan Syndrome; I.Q. scores vary from 50 to 119 (normal is 85 to 115). Approximately one-third of individuals with Noonan Syndrome are mildly mentally retarded (i.e. having an I.Q. between 69-52), however, individuals with superior intelligence are also described. Delay in language acquisition is by far the most common problem (25%) with the majority of children having difficulties with articulation. These respond well to speech therapy.

The frequency of Noonan Syndrome may be as high as 1 per 1000 live births. Early reports suggested that most cases of Noonan Syndrome were sporadic (occurring once in a family) however, this condition is now clearly caused by a different gene. All of our genes are in pairs, with one inherited from our mother and one from our father. This gene is strong, or dominant, so only one of the pair needs to be faulty for it to show itself.

An affected parent has a 50% (1 in 2) chance to pass on the gene to his / her child. Perhaps 1 case in 4 is caused by a new mutation or change in the genetic information. Women appear to pass on the different gene three times more often than men. This phenomenon is attributed to reduced fertility in men, possibly as a result of persistent cryptorchidism. As stated earlier, chromosome analysis in people with Noonan Syndrome is normal.

Is there a cure?
There is no cure for Noonan Syndrome, but a number of complications of Noonan Syndrome can be treated by surgery, medicine, special education, or speech therapy. A proportion of the heart defects require surgical correction. Surgery may also be performed to correct pectus excavatum and pectus carinatum, strabismus and ptosis, inguinal hernias and undescended testicles.

Medical treatment can be used to correct the mild blood clotting problems associated with Noonan Syndrome. Growth hormone supplementation in patients with Noonan Syndrome may be possible if growth hormone deficiency is shown. Special education classes and/or speech therapy may be needed. Orthodontic treatment of malocclusion is recommended. Hopefully, the future will provide answers about the cause of Noonan Syndrome so that specific forms of therapy may be available.

Can Noonan Syndrome be diagnosed during" pregnancy?
Until the gene is localized and isolated, no foolproof method of prenatal diagnosis will be available. However, high resolution ultrasound is recommended, beginning at about 16 weeks gestation, looking for edema, a cystic swelling in the neck area (cystic hygroma), excessive amniotic fluid (polyhydramnios) and marked accumulation of fluid by the fetus (hydrops). All these features have been previously described in Noonan Syndrome, but, as yet, we do not know how common they are. For this reason, absence of these ultrasound findings does not guarantee an unaffected fetus.

What research is being conducted?
Research into growth hormone deficiency as a cause of growth delay in Noonan Syndrome has already been mentioned. In addition, various teams in the United States and United Kingdom are trying to locate and isolate the different gene which causes Noonan Syndrome. This may lead to a better understanding of the cause of the various physical features and birth defects accompanying this condition and, perhaps, a means of intervention.

Common reactions of parents of Patients with Noonan Syndrome:
Parents may feel responsible for their child having an unusual condition. Initially, the parents may deny the existence of the Syndrome or may feel numb and helpless. These feelings may turn to anger and sadness. A parent who shares similar features to his/her child may feel even more responsible. Parents may also feel ashamed because they have not produced a normal child. These are normal reactions to the birth of a child with a difference.

The majority of parents do not need therapeutic counselling, but social workers, psychologists, and members of the clergy can all help in coping with the impact of this diagnosis. Meetings with parents who are going through or have already gone through similar experiences may also help in sharing these reactions. It is essential for the parents to face their fears and to openly discuss their feelings among themselves and with others.

What are some common family concerns?
The entire family is affected by the diagnosis of Noonan Syndrome. Couples may experience a strain in their relationship when they first learn of the diagnosis. Grandparents may feel responsible or may try to place blame on parents or "on the other family". They may go through the same stages as the parents do, and thus must learn to communicate their fears and seek support from appropriate people. Unaffected sisters and brothers need support too. They may feel guilty that they don't have Noonan Syndrome. Siblings also need to communicate and talk about their feelings. They must be encouraged to ask questions. They should learn to trust their sibling as a normal individual and not a 'person with a Syndrome.'Siblings may also resent the amount of attention given to an affected individual. Parents must be ready to compensate for this.

What are some common reactions of patients?
Most patients are diagnosed at an early age, however, some adults may only be recognized through the diagnosis of their child. These individuals may suddenly feel that they look different and may be self-conscious. They may feel depressed and ask "why" and "what did I do to deserve this'. They may also feel guilty about passing on the gene to their child. It must be emphasized that we have no control over our genetic make-up.

How is the physician involved in patient care?
Every person needs a physician who can care for routine medical illnesses and can coordinate comprehensive medical care. Most primary care physicians know little about Noonan Syndrome, thus a team approach is needed. In addition to the primary care giver (internist, paediatrician, family practitioner), the team must include a physician who feels comfortable with the diagnosis and care of Noonan Syndrome patients (dysmorphologist, clinical geneticist). The primary care giver can utilize specialities which may include plastic surgery, thoracic (cardiac) surgery, general surgery, obstetrics, psychiatry, haematology, speech therapy and others. A team approach will allow optimal medical care and intervention for the patient with Noonan Syndrome.

The Noonan Syndrome Support Group, Inc. and any associated parties will not be held responsible for any actions readers take based on their interpretation of published or disseminated material. Please review medical treatment and decisions with your physician.