Noonan syndrome

Noonan Syndrome (NS) is a relatively common autosomal dominant congenital disorder considered to be a type of dwarfism, that affects both males and females equally. It used to be referred to as the male version of Turner's syndrome (and is still sometimes described in this way); however, the genetic causes of Noonan syndrome and Turner syndrome are distinct. The principal features include congenital heart defect (typically pulmonary valve stenosis), short stature, learning problems, pectus excavatum, impaired blood clotting, and a characteristic configuration of facial features including a webbed neck and a flat nose bridge. The syndrome is named after Dr. Jacqueline Noonan.

It is believed that between approximately 1 in 1,000 and 1 in 2,500 children worldwide are born with NS. It is one of the most common genetic syndromes associated with congenital heart disease, similar in frequency to Down syndrome. However, the range and severity of features can vary greatly in patients with NS. Therefore, the syndrome is not always identified at an early age.

Characteristics
Often called a "hidden" condition, the person affected may have no obvious casual signs to the onlooker, but the problems may be many and complex. The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

Heart

 * 2/3 of patients have one of the following heart defects:
 * Pulmonary Valvular Stenosis &mdash;(50%)
 * Septal defects: atrial &mdash;(10%) or ventricular &mdash;(less common)
 * Heart murmur
 * Cardiomyopathy

Gastrointestinal system

 * Failure to thrive as an infant
 * Decreased appetite
 * Digestive problems
 * Frequent or forceful vomiting
 * Swallowing difficulties

Genito-urinary system

 * Cryptorchidism (undescended testicles) &mdash;

Lymphatic system

 * Posterior cervical hygroma (webbed neck)
 * Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)

Developmental

 * Clumsiness
 * Poor coordination
 * Motor delay
 * Mental retardation &mdash;(1/3 of patients have mild MR)
 * Learning disabilities
 * Speech and language delays

Musculoskeletal

 * Some patients with Noonan Syndrome suffer from severe joint pain or muscle pain often with no identifiable cause

Hematologic

 * Easy bruising
 * Amegakaryocytic Thrombocytopenia (low platelet count)
 * Blood Clotting Disorders
 * Von Willebrand disease
 * Prolonged activated partial thromboplastin time
 * Partial deficiency of Factor VIII:C
 * Partial deficiency of Factor XI:C
 * Partial deficiency of Factor XII:C
 * Combined Coagulation deficiencies

Neurological
Arnold-Chiari Malformation (Type 1) has been noted in some patients with Noonan Syndrome

Stature and posture

 * Short stature
 * Cervical (neck) spine fusion
 * Scoliosis
 * Prominence of breast bone (pectus carinatum)
 * Depression of breast bone (pectus excavatum)
 * Joint contractures or tightness
 * Joint hyperextensibility or looseness
 * Growth retardation
 * Winging of the scapula
 * Hypotonia (low muscle tone)

Head

 * Excess skin on the back of the neck
 * Low hairline at the nape of the neck
 * High hairline at the front of the head
 * Large head
 * Triangular face shape
 * Broad forehead
 * Short neck, webbed neck, posterior cervical
 * Curly hair

Eyes

 * Widely set eyes (hypertelorism) &mdash;(95%)
 * Drooping of the eyelids (ptosis (eyelid))
 * Epicanthal folds (extra fold of skin at the inner corner of the eye)
 * Proptosis (bulging eyes)
 * Refractive visual errors
 * Inward or outward turning of the eyes (strabismus)
 * Nystagmus - jerking movement of the eyes

Nose

 * Small, upturned nose

Ears and hearing

 * Low set ears &mdash;(over 90%)
 * Backward rotated ears &mdash;(over 90%)
 * Thick helix of ear (outer rim) &mdash;(over 90%)
 * Incomplete folding of ears
 * Chronic Otitis media (ear infections)

Mouth and speech

 * Deeply grooved philtrum (top lip line) &mdash;(over 90%)
 * Micrognathia (undersized lower jaw)
 * High Arched palate
 * Dental problems
 * Articulation Difficulties
 * Poor tongue control

Limbs/extremities

 * Bluntly ended fingers
 * Extra padding on fingers and toes
 * Edema of the back of hands and tops of feet
 * Cubitus valgus (elbow deformity: with abnormal turning-in)

Skin

 * Lymphedema (swelling of the extremities)
 * Keloids (scar hypertrophy)
 * Hyperkeratosis - overdevelopment of outer skin layer
 * Pigmented nevi (birthmark)

Cause
Recurrence in siblings and apparent transmission from parent to child has long suggested a genetic defect with autosomal dominant inheritance and variable expression. A person with NS has up to a 50% chance of transmitting it to a child. The fact that an affected parent is not always identified for children with NS suggests several possibilities:
 * 1) manifestations are variably expressed and could be so subtle as to go unrecognized (variable expressivity)
 * 2) a high proportion of cases represent new, sporadic mutations or
 * 3) Noonan syndrome is heterogeneous, comprising more than one similar condition of differing cause, some not inherited.

A condition known as "neurofibromatosis-Noonan syndrome" is associated with neurofibromin.

Diagnosis
Despite identification of four causative genes, the diagnosis of Noonan syndrome is still based on clinical features. In other words, it is made when a physician feels that a patient has enough of the features to warrant the label indicating association. The patient can be screened for mutations in the PTPN11, SOS1, or KRAS genes, however absence of a mutation will not exclude the diagnosis as there are more as yet undiscovered genes that cause NS. The principal values of making such a diagnosis are that it guides additional medical and developmental evaluations, it excludes other possible explanations for the features, and it allows more accurate recurrence risk estimates.

History
Jacqueline Noonan was practicing as a pediatric cardiologist at the University of Iowa when she noticed that children with a rare type of heart defect, valvular pulmonary stenosis, often had a characteristic physical appearance with short stature, webbed neck, wide spaced eyes, and low-set ears. Both boys and girls were affected. Even though these characteristics were sometimes seen running in families, chromosomes appeared grossly normal. She studied 833 patients at the congenital heart disease clinic, looking for other congenital abnormalities, and in 1962 presented a paper: "Associated non-cardiac malformations in children with congenital heart disease". This described 9 children who in addition to congenital heart disease had characteristic faces, chest deformities and short stature. Both males and females were found to be similarly affected, and the chromosomes were apparently normal.

Dr. John Opitz, a former student of Dr. Noonan, first began to call the condition "Noonan Syndrome" when he saw children who looked like those whom Dr. Noonan had described. Dr. Noonan later produced a paper entitled "Hypertelorism with Turner Phenotype", and in 1971 at the Symposium of Cardiovascular defects, the name 'Noonan Syndrome' became officially recognized.