Noonan syndrome

Phenotype and clinics	Noonan syndrome is a clinically variable developmental disorder defined by short stature, facial dysmorphism and a wide spectrum of congenital heart defects. The distinctive facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high-arched palate and low-set, posteriorly rotated ears. Cardiovascular abnormalities, primarily pulmonic stenosis and hypertrophic cardiomyopathy, are present in up to 85% of affected individuals. Additional relatively frequent features are multiple skeletal defects (spine and chest), webbed neck, mental retardation, cryptorchidism and bleeding diathesis.
	Clinical features in Noonan syndrome. (A) Prenatal echography showing nuchal cystic hygroma; (B) dysmorphic facial features; (C) pectus deformities and cubitus valgus; (D) webbed neck; (E) schematic representation of major cardiac defects: 1, pulmonic stenosis; 2, hypertrophic cardiomyopathy; 3, atrial septal defects; 4, ventricular septal defects; 5, patent ductus arteriosus. (Figures kindly provided by G. Zampino, MD, Università Cattolica del Sacro Cuore, Rome, Italy).
Neoplastic risk	Children with Noonan syndrome are predisposed to malignancies, juvenile myelomonocytic leukemia (JMML) most commonly. JMML, formerly termed juvenile chronic myeloid leukemia or chronic myelomonocytic leukemia, is a myeloproliferative/myelodysplastic disorder of childhood characterized by excessive proliferation of immature and mature myelomonocytic cells that originate from a pluripotent stem cell. In childhood, JMML accounts for approximately 30% of cases of myelodysplastic and myeloproliferative syndromes and 2% of leukemias. It typically presents in infancy and early childhood, and is often lethal. Recent studies have provided strong evidence that hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), due to a selective inability to down-regulate the RAS/MAPK cascade, plays a central role in the clonal cell growth characteristic of JMML. In approximately 15-30% of JMML cases, the pathological activation of the RAS/MAPK cascade results from oncogenic NRAS or KRAS2 mutations that specifically affect GTP hydrolysis, leading to the accumulation of RAS in the GTP-bound active conformation. JMML has been reported in children with neurofibromatosis type 1 (NF1), an autosomal dominant disorder resulting from germline loss-of-function mutations of the NF1 tumor suppressor gene. In children with NF1 and JMML, the proliferative advantage of the leukemic cells results from a second hit, the somatic loss or inactivation of the normal NF1 allele. Since the NF1 gene product, neurofibromin, is a negative modulator of RAS function, this loss is associated with RAS hyperactivity. Remarkably, deregulated RAS function appears to be restricted to GM-CSF signaling in hematopoietic cells. More recently, somatic activating mutations in the PTPN11 gene, which encodes the protein tyrosine phosphatase (PTP) SHP-2, have been documented in approximately 35% of cases with JMML. Mutations in the PTPN11, RAS and NF1 genes are largely mutually exclusive in JMML, and their combined prevalence accounts for approximately 85% of cases. Acute lymphoblastic leukemia and solid tumors, particularly neuroblastoma and rhabdomyosarcoma, have also been documented with a relatively higher prevalence respect to the general population.
Evolution	In children with Noonan syndrome JMML may regress without treatment or follow an aggressive clinical course. By contrast, cases of JMML that arise in children without Noonan syndrome have a poor prognosis without hematopoietic stem cell transplantation.

DNA/RNA
	The PTPN11 gene and SHP-2 domain characterization. The coding exons are shown as numbered filled boxes. The functional domains of the protein, comprising two amino-terminal, tandemly arranged SH2 domains (N-SH2 and C-SH2) followed by a protein tyrosine phosphatase (PTP) domain, are shown below. Numbers below the domain structure indicate the amino-acid boundaries of those domains.
Description	The PTPN11 gene counts 16 exons. Exon 1 contains the 5'-UTR and the translation initiation ATG, and a few additional codons. Exon 15 contains the stop codon and exon 16 contains a major portion of the 3'-UTR. Other features of the PTPN11 gene, such as the promoter region and enhancer elements have not been delineated.
Transcription	A 7.0-kb transcript is detected in several tissues (heart, brain, lung, liver, skeletal muscle, kidney, and pancreas) with highest steady-state levels in heart and skeletal muscle. The predominant human PTPN11 mRNA contains an open reading frame of 1,779 bases, resulting in a predicted protein of 593 amino acid residues.
Pseudogene	A number of speudogenes, sharing more than 92% nucleotide identity with PTPN11 cDNA (including the untranslated regions), have been documented in the human genome. All the pseudogenes harbour frameshift mutations and multiple stop codons. Three of the five pseudogenes are likely to be expressed but with distinct tissue distribution and expression level.

Protein
	Figure 3: Three-dimensional structure of SHP-2 in its catalytically inactive conformation, as determined by Hof and co-workers. Residues involved in catalysis are shown (space fill). Figure 4: Location of SHP-2 mutated residues in human disease. (A) Noonan syndrome and LEOPARD syndrome (germ-line origin; N=224); (B) Noonan syndrome with juvenile myelomonocytic leukemia (germ-line origin; N=11); (C) hematologic malignancies, including juvenile myelomonocytic leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia (somatic origin; N=97). The pictures show the Ca trace of SHP-2 in its catalytically inactive conformation. Affected residues are indicated with their side chains as black sticks.
Description	SHP-2 is a member of a small subfamily of cytoplasmic Src homology 2 (SH2) domain-containing protein tyrosine phosphatases. The amino-terminal SH2 (N-SH2 and C-SH2) domains selectively bind to short amino acid motifs containing a phosphotyrosyl residue and promote SHP-2 association with cell surface receptors, cell adhesion molecules and scaffolding adapters. Crystallographic data indicate that the N-SH2 domain also interacts with the PTP domain using a separate site. As these subdomains show negative cooperativity, the N-SH2 domain functions as an intramolecular switch controlling SHP-2 catalytic activation. Specifically, the N-SH2 domain interacts with the PTP domain basally, blocking the catalytic site. Binding of the N-SH2 phosphopeptide-binding site to the phosphotyrosyl ligand promotes a conformational change of the domain that weakens the auto-inhibiting intramolecular interaction, making the catalytic site available to substrate, thereby activating the phosphatase.
Expression	Widely expressed in both embryonic and adult tissues.
Localisation	Cytoplasmic. It binds to activated cell surface receptors, cell adhesion molecules and scaffolding adapters. Phosphorylation of two tyrosine residues at the C-terminus by activated tyrosine kinase receptors creates binding sites for other SH2 domain-containing signal transducers.
Function	SHP-2 functions as a intracellular signal transducer. It positively modulates signal flow in most circumstances, but can also function as negative regulator depending upon its binding partner and interactions with downstream signaling networks. SHP-2 positively controls the activation of the RAS/MAPK cascade induced by several growth factors, and negatively regulates JAK/STAT signaling. In most cases, SHP-2's function in intracellular signaling appears to be immediately proximal to activated receptors and upstream to RAS. The mechanisms of SHP-2's action and its physiological substrates are still poorly defined. However, both membrane translocation and PTPase activity are required for SHP-2 function. SHP-2 is required during development. Embryos nullizygous for Shp-2 have defects in gastrulation and mesodermal patterning resulting in severe abnormalities in axial and paraxial mesodermal structures. Shp-2 function is also required for development of terminal and skeletal structures, semilunar valvulogenesis in the heart, and hematopoiesis.
Homology	PTPN6 (protein tyrosine phosphatase, non-receptor type, 6) previously known as SHP1 or SHP-1 (Src homology 2 domain-containing protein tyrosine phosphatase, 1).

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