English Version
S. J. S. Bajwa, R. Haldar

Noonan syndrome

Noonan syndrome

Schlüsselwörter Noonan syndrome; ICD 10: Q87.1
Keywords Noonan syndrome; ICD 10: Q87.1
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Koblinsky first described this syndrome in 1883. The term “Noonan syndrome” was first used in 1963 when Jacqueline Noonan and Dorothy Ehmke described nine children with a combination of congenital heart defect, short stature and characteristic appearance. Originally, these patients were thought to resemble patients with Turner syndrome, despite having a normal karyotype. Patients with Noonan syndrome (NS) typically have characteristic facial, cardiovascular, and skeletal/growth abnormalities. The disease is transmitted as an autosomal dominant trait but the majority of the cases are sporadic due to de novo mutations.

Incidence has been estimated in between 1:1,000 and 1:2,500 without gender preponderance. Mutations in various components of the RAS-MAPK signaling pathway are known to cause Noonan syndrome [1] . Around 50% of patients with Noonan syndrome have  mutations of the PTPN11 gene which encodes for a protein called SHP-2. Noonan syndrome-associated mutations cause the SHP-2 protein to be continuously active, rather than switching on and off in response to other cellular proteins.  This constant activation results in aberrant activation and upregulation of RAS signalling, and disrupts the regulation of systems that control cell functions such as growth and division and result in the abnormal features common to Noonan syndrome by mechanisms that are incompletely understood.

The diagnosis of Noonan syndrome is primarily clinical. Diagnostic criteria have been suggested by van der Burgt [1]. Nowadays, molecular testing offers the opportunity to confirm the diagnosis in the majority of patients.  The craniofacial features of Noonan syndrome include hypertelorism, down slanting palpebral fissures with high arched eyebrows, epicanthic folds, a depressed nasal root with a wide nasal base, a full upper lip, dental malocclusion, a high arched palate, micrognathia, and a broad or webbed neck. Cardiac anomalies like pulmonary valve stenosis (commonest 50-60%), hypertrophic cardiomyopathy (20%), atrial septal defects (8%), ventricular septal defects (5%), and patent ductus arteriosus (3%)  are commonly present.

About half of patients with Noonan syndrome have an unusual electrocardiographic pattern characterized by left-axis deviation, an abnormal R/S ratio over the left precordial leads, and an abnormal Q wave. Cardiac rhythm disturbance may occur particularly in patients with hypertrophic cardiomyopathy. Growth delay usually is of postnatal onset, and short stature is of mild to moderate degree and proportionate. Relative macrocephaly is frequent. Other commonly associated anomalies may include feeding difficulties during infancy and childhood, gastroesophageal reflux and cryptorchidism in males. Pectus carinatum or excavatum, cubitus valgus and spina bifida, and other vertebral and rib anomalies are common skeletal changes in Noonan syndrome. However, there is no evidence that true spinal malformations (haemivertebrae and spina bifida) are really associated with RASopathies.

Abnormal bleeding is a frequent accompaniment. Coagulation screens may show variable abnormalities such as a prolonged prothrombin time (PTT), activated partial thromboplastin time, platelet count, or bleeding time. Approximately 25% of individuals with Noonan syndrome have been reported to have partial factor XI deficiency, but various other coagulation deficits have been observed, for which an accurate estimate of the prevalence is not available (e.g. low factor XII and factor VIII activity, von Willebrand disease, rarely factor IX and factor II deficiencies). Further variable features include deficits in psychomotor and cognitive development, ocular abnormalities, dermatologic symptoms (hyperkeratosis, eczema), lymphedema, and renal anomalies. Occasionally, Noonan syndrome may be associated with malignancy (particularly leukaemia), a transient myeloproliferative disorder of infancy, jaw tumours (multiple giant cell lesions), hydrocephalus, Arnold-Chiari I malformation, and atlanto-axial dislocation. The multisystem involvement makes the anaesthetic management of these patients demanding.


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