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Noonan syndrome

From Biocrawler, the free encyclopedia.

Noonan Syndrome (NS) is a relatively common congenital genetic condition which affects both males and females. The principal features include congenital heart malformation, short stature, learning problems, indentation of the chest, impaired blood cloting, and a characteristic configuration of facial features. NS is one of the most common conditions associated with congenital heart anomalies, especially those of the right heart. The syndrome is named after Dr Jacqueline Noonan, a paediatric cardiologist based in Kentucky.

It is believed that 1 in 1,000 to 1 in 2,500 children worldwide are born with Noonan syndrome. It is one of the most common genetic syndromes associated with congenital heart malformations, similar in frequency to Down syndrome. However, the body features are much less obviously abnormal, and many if not most affected persons go undiagnosed.

Contents

1 Cause

2 Manifestations by organ system

2.1 By physical appearance

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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 clearly affected person had up to a 50% chance of transmitting it to a child. The fact that affected parents cannot be identified for many children with Noonan syndrome suggests that (1) a parent could carry the gene without being affected, (2) that manifestations were variably expressed and could be so subtle as to go unrecognized, (3) that a high proportion of cases represented new, sporadic mutations, or (4) that Noonan syndrome is heterogeneous, comprised of more than one similar condition of differing cause, some not inherited.

In most of the families with multiple affected members, Noonan syndrome mapped to chromosome 12q24.1 In 2001, it was reported that approximately half of a group of patients with Noonan syndrome carried a mutation of the PTPN11 gene at that location, which encodes protein tyrosine phosphatase SHP-2 (Tartaglia M, et al. Nature Genetics 2001;29:465-468). The protein SHP-2 is a component of several intracellular signal transduction systems involved in embryonic development that modulate cell division,differentiation, and migration, including that mediated by the epidermal growth factor receptor. The latter pathway is important in the formation of the cardiac semilunar valves.

Noonan syndrome has been assigned OMIM number 163950 [1] (http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=163950).

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Manifestations by organ system

The most prevalent (common) signs are highlighted in bold with frequency listed in parentheses.

HEART —(2/3 of pts have a heart defect)

Pulmonary Valvular Stenosis —(50%)

Septal defects: atrial —(10%) or ventricular —(less common)

Heart Murmur

Cardiomyopathy

GASTROINTESTINAL SYSTEM

Failure to thrive as an infant

Decreased appetite

Fatty eater

Digestive/Intestinal problems

Frequent or forceful vomiting

Swallowing difficulties

GENITO-URINARY SYSTEM

Cryptorchidism (undescended testicles) — (almost all males)

LYMPHATIC SYSTEM

Posterior Cervical Hygroma (webbed neck)

Lymphedema (build-up of body fluid due to poor functioning of the lymphatic system)

DEVELOPMENTAL

Delayed puberty

Lack of sexual development

Clumsiness

Poor coordination

Motor delay

Mental retardation —(1/3 of pts have mild MR)

Learning disabilities

Speech and language delays

MUSCULOSKELETAL

Severe joint or muscle pain

Osteoporosis

HEMATOLOGIC —(1 in 5 pts have a bleeding disorder)

Easy bruising

Vasculitis (blood vessel inflammation; many types and causes)

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

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By physical appearance

STATURE/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)

Distended abdomen

HEAD

Excess skin on the back of the neck

Low hairline at the nape of the neck

Large Head

Small Head (microcephaly)

Triangular face shape

Broad forehead

Short neck, webbed neck, posterior cervical

Curly Hair

EYES

Widely set eyes (hypertelorism) —(95%)

Drooping of the eyelids (ptosis)

Epicanthal folds (extra fold of skin at the inner corner of the eye)

Diamond shaped eyebrows

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/HEARING

Low set ears —(over 90%)

Backward rotated ears —(over 90%)

Thick helix of ear (outer rim) —(over 90%)

Incomplete folding of ears

Chronic Otitis media (ear infections)

Glue Ear (thick glue-like fluid behind ear drum)

MOUTH/SPEECH

Deeply grooved philtrum (top lip line) —(over 90%)

Micrognathia (small mouth)

High Arched palate

Dental problems

Hypernasality

Articulation Difficulties

Poor tongue control

LIMBS/EXTREMITIES

Bluntly ended fingers

Extra padding on fingers and toes

Simian creases; deeply grooved palms and bottoms of feet

Edema of the back of hands and tops of feet

Cubitus Valgus (elbow deformity)

Polydactyly (having extra fingers or toes)

SKIN

Hirsutism (excessive body hair growth)

Cutaneous Lymphangioma (wart-like growth on the skin, very small, made up of abnormal lymph vessels)

Keloids (scar hypertrophy)

Hyperkeratosis - overdevelopment of outer skin layer

Pigmented nevi (birthmark)

Vitiligo (unpigmented patches on the skin)

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Diagnosis

Despite identification of a candidate gene, 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. It is likely that a specific gene test will become available soon, but absence of the specific mutation will not exclude the diagnosis. The principal values of making such a diagnosis are that it suggests other problems to check for, it excludes other possible explanations for the features, and it suggests the possibility of recurrence risk in siblings or offspring of the patient.

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Treatment

Each specific abnormality can be treated as if it occurred in isolation. A congenital heart malformation can be corrected surgically. Undescended testes can be brought into the scrotum surgically. Growth hormone is sometimes given to improve shortness. Learning problems should be ameliorated by determining a child's optimal learning conditions. Behavior problems can usually be helped by counseling the family.

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History

The first description of a patient with the features of Noonan syndrome was made by Koblinsky in 1883, although it was not until the late 1960's that the condition became commonly referred to as Noonan syndrome.

Jacqueline Noonan is a pediatric cardiologist and pediatrician, now based in Kentucky, who qualified in Boston in 1956. When she subsequently began work at the University of Iowa as their first pediatric cardiologist, 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.

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