[PTPN11 and the deafness].

Summary PTPN11 gene encodes tyrosine phosphatase SHP-2 which locates on chromosome 12（12q24.1）, expresses in most embryonic and adult tissues, and plays pivotal roles in cell proliferation, differentiation, survival and cell death. SHP-2 apparently participates in signaling events downstream of RAS-MAPK and JAK/STAT. Diseases related to PTPN11 gene mutations include the Noonan syndrome（NS） and the NS with Multiple Lentigines（NSML）. Both NS and NSML contain the phenotypes of deafness, craniofacial anomalies, short stature, congenital heart defects, skin disorders, ophthalmologic abnormalities and cancer predisposition.

[RAS/MAPK signal transduction pathway and its role in the pathogenesis of Noonan syndrome]. / Sciezka sygnalowa RAS/MAPK i jej rola w etiopatogenezie zespolu Noonan.

Noonan syndrome (NS) is one of the most frequent dysmorphic syndromes in children with a frequency of 1/1000-1/2500 of newborns. Noonan syndrome is a multi-organ disease with a broad spectrum of clinical symptoms. The most characteristic features of NS are: craniofacial dysmorphy, short stature, cardiovascular defects, bone and skeletal defects and delayed puberty (cryptorchidism in males). Noonan syndrome has a genetic background and is inherited in autosomal dominant manner. The recent studies have shown that it is due to the presence of mutation in one of the genes encoding proteins of RAS/MAPK signalling pathway responsible for cell proliferation and differentiation. Till now, NS causing mutations were identified in PTPN11, SOS1, RAF1, KRAS, BRAF, SHOC2 and NRAS genes, and this may partially explain the broad phenotypic spectrum observed in patients. Noonan syndrome is one of the RAS-opathies, therefore the molecular analysis of RAS/ MAPK genes might be a very useful tool in clinical differentiation of the disease.

[Noonan's syndrome and growth hormone treatment]. / Syndrome de Noonan et hormone de croissance.

Noonan's syndrome is a clinical entity associating short stature, facial dysmorphy and congenital cardiomyopathy. In 50 % of cases, PTPN11 mutations are found, transmitted as an autosomal dominant trait. Mutations of other genes (KRAS, SOS1) were also recently reported. Short stature could be due to GH deficiency, abnormal neurosecretory function or GH insensitivity. GH treatment induces height gain, even if only few studies reported data on final height. Response to GH varies, depending on the presence of PTPN11 mutations. No cardiac adverse effects were reported to date with GH treatment in Noonan's syndrome.

The spectrum of cardiac anomalies in Noonan syndrome as a result of mutations in the PTPN11 gene.

OBJECTIVE: Noonan syndrome is a clinically homogeneous but genetically heterogeneous condition. Type 1 Noonan syndrome is defined by the presence of a mutation in the PTPN11 gene, which is found in approximately 40% of the cases. Phenotype descriptions and cardiac defects from cohorts with Noonan syndrome were delineated in the "pregenomic era." We report the heart defects and links to gene dysfunction in cardiac development in a large cohort of patients with type 1 Noonan syndrome. METHODS: This was a retrospective, multicenter study based on clinical history, pictures, and medical and cardiologic workup over time. Data were collected by referral geneticists. Mutation screening was performed by direct sequencing of exons 2, 3, 4, 7, 8, 12, and 13 and their intron-exon boundaries, which harbor 98% of identified mutations the PTPN11 gene. RESULTS: A PTPN11 gene mutation was identified in 104 (38.25%) of 274 patients with Noonan syndrome. Heart defect was present in 85%. The most prevalent congenital heart defects were pulmonary valve stenosis (60%), atrial septal defect, ostium secundum type (25%), and stenosis of the peripheral pulmonary arteries (in at least 15%). Pulmonary valve stenosis and atrial septal defect, ostium secundum type, were significantly associated with the identification of a mutation in the PTPN11 gene. Ventricular septal defect and most left-sided heart defects showed a trend toward overrepresentation in the group without a mutation. CONCLUSION: We compared our data with previous series and integrated the comprehension of molecular PTPN11 gene dysfunction in heart development.

Type 1 Arnold-Chiari malformation and Noonan syndrome. A new diagnostic feature?

Noonan syndrome is a clinically and genetically heterogeneous genetic condition. Arnold-Chiari malformation has been previously reported in three cases of Noonan syndrome. We describe a fourth case with this association. We suggest that brain and cervical spine MRI should be performed if neurological symptoms are present.

King syndrome: further clinical variability and review of the literature.

The King syndrome is characterized by a Noonan-like phenotype, the presence of a nonspecific myopathy and a predisposition to malignant hyperthermia. In some families, mild physical manifestations of the phenotype and/or elevated serum creatine phosphokinase (CPK) in relatives suggest the presence of an autosomal dominant myopathy with variable expressivity. We summarize the cases of 14 previously reported patients and describe a new patient, a 7-year-old girl, with the King syndrome and the unique findings of diaphragmatic eventration, tethered spinal cord, and severe paucity of type 2 skeletal muscle fibers. It has been proposed that the King syndrome represents a common phenotype that may result from several different slowly progressive congenital myopathies. This hypothesis, and the phenotypic overlap between the King and Noonan syndromes are discussed in light of the findings in this new patient.

The cardio-facio-cutaneous syndrome: a manifestation of the Noonan syndrome?

The cardio-facio-cutaneous (CFC) syndrome has several features in common with the Noonan syndrome, but is distinguished by the presence of hyperkeratotic skin lesions, abnormal hair, and a lack of familial cases. We describe a family who clearly satisfy the criteria for the CFC syndrome, and show other features which have been reported in the Noonan syndrome but not in the CFC syndrome, namely a haemorrhagic diathesis and ocular abnormalities. This supports the concept that the CFC syndrome is a manifestation of the Noonan syndrome.

A Noonan-like short stature syndrome with sparse hair.

Noonan's syndrome is a clinically recognisable short stature syndrome with autosomal dominant inheritance. The diagnosis can be difficult as the phenotypic expression is very variable. There has been an attempt to divide this syndrome into type I (in which the facial features, especially ptosis, antimongoloid eye slant, and hypertelorism are prominent) and type II (where cardiological abnormalities are more to the fore), but this has not yet been confirmed by other studies.