Noonan syndrome: coagulation and clinical aspects

Massarano, A. A.; Wood, A. Jamie; Tait, RC; Stevens, R. F.; Super, Maurice

doi:10.1111/j.1651-2227.1996.tb18225.x

Cited by 34 publications

(14 citation statements)

References 21 publications

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“…The most common abnormalities include von Willebrand disease, deficiencies of factors XI and XII, and thrombocytopenia [Sharland et al, 1992b;Massarano et al, 1996;Singer et al, 1997]. Since many affected children will require interventional procedures such as balloon pulmonary valvuloplasty and orchidopexy, this is important to bear in mind to prevent significant hemorrhagic complications.…”

Section: Clinical Featuresmentioning

confidence: 99%

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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Noonan syndrome (NS) is a relatively common, clinically variable and genetically heterogeneous developmental disorder characterized by postnatally reduced growth, distinctive facial dysmorphism, cardiac defects and variable cognitive deficits. Other associated features include ectodermal and skeletal defects, cryptorchidism, lymphatic dysplasias, bleeding tendency, and, rarely, predisposition to hematologic malignancies during childhood. NS is caused by mutations in the PTPN11, SOS1, KRAS, RAF1, BRAF and MEK1 (MAP2K1) genes, accounting for approximately 70% of affected individuals. SHP2 (encoded by PTPN11), SOS1, BRAF, RAF1 and MEK1 positively contribute to RAS-MAPK signaling, and possess complex autoinhibitory mechanisms that are impaired by mutations. Similarly, reduced GTPase activity or increased guanine nucleotide release underlie the aberrant signal flow through the MAPK cascade promoted by most KRAS mutations. More recently, a single missense mutation in SHOC2, which encodes a cytoplasmic scaffold positively controlling RAF1 activation, has been discovered to cause a closely related phenotype previously termed Noonan-like syndrome with loose anagen hair. This mutation promotes aberrantly acquired N-myristoylation of the protein, resulting in its constitutive targeting to the plasma membrane and dysregulated function. PTPN11, BRAF and RAF1 mutations also account for approximately 95% of LEOPARD syndrome, a condition which resembles NS phenotypically but is characterized by multiple lentigines dispersed throughout the body, café-au-lait spots, and a higher prevalence of electrocardiographic conduction abnormalities, obstructive cardiomyopathy and sensorineural hearing deficits. These recent discoveries demonstrate that the substantial phenotypic variation characterizing NS and related conditions can be ascribed, in part, to the gene mutated and even the specific molecular lesion involved.

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Section: Clinical Featuresmentioning

confidence: 99%

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

2010

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“…Later studies showed a high frequency (56-67%) of coagulation defects in this patient group [Sharland et al, 1992;Massarano et al, 1996;Singer et al, 1997]. Sharland et al [1992] did detailed coagulation studies on 72 individuals with NS.…”

Section: Discussionmentioning

confidence: 96%

“…The same study reported combined FXI and FXII deficiency in one patient, combined FXI and FVIII deficiency in another patient, and combined FVIII, FXI, and FXII deficiencies in a third patient. Massarano et al [1996] investigated 18 patients with NS and found increased bruising or bleeding in 12 (67%). They detected prolonged aPTT in 10 cases (56%) linked with low activity levels of clotting factors, particularly FXI and FXII.…”

Section: Discussionmentioning

confidence: 97%

Clinical and hematologic findings in Noonan syndrome patients with PTPN11 gene mutations

Derbent

Öncel

Tokel

et al. 2010

American J of Med Genetics Pt A

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Reports on Noonan syndrome (NS) have documented multiple types of coagulation defects and bleeding diathesis, and a wide range of clinical presentations. Early studies suggested that a large proportion of NS patients have coagulation defects, whereas more recent reports indicate low rates of coagulopathy. The aim of this study was to evaluate phenotypic characteristics, PTPN11 gene mutations, and hematological and coagulation parameters in 30 clinically diagnosed cases of NS. One of the NS patients had a history of easy bruising; however, his hematological and coagulation tests were normal. None of the other patients had clinical coagulation problems. In the NS group, values for platelet count, activity of factors XI, XII, and protein C were significantly lower than the corresponding means for the control group. However, the results of coagulation tests in the NS group were diagnostically inconclusive and only one patient had clinical signs of coagulopathy. Interestingly, two NS patients had low protein C activity. One of these children had an A1517C mutation and transient myelodysplasia. The other patient had a C1528G mutation in exon 13 that has not been reported previously. Neither of these individuals experienced a thrombotic event or any complication during approximately 3 years of follow-up. For all patients clinically diagnosed with NS, a thorough history of coagulation issues should be taken and first-line coagulation testing should be done to evaluate for bleeding diathesis. However, if these assessments reveal nothing abnormal, complications related to coagulation are unlikely and extensive testing is unnecessary.

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“…Easy bruising and bleeding problems have been reported in up to 55% of patients. Coagulation studies reveal prolonged bleeding time, factor VIII, XI and XII deficiencies, thrombocytopenia and platelet function defects [8][9][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…Noonan Syndrome (NS) is an autosomal dominant disorder characterized by short stature, typical facial dysmorphisms, congenital heart defects and other anomalies [8][9][10] such as bleeding problems which have been reported in up to 55% of patients [8][9][10][11][12][13][14]. NS is a clinical diagnosis.…”

Section: Introductionmentioning

confidence: 99%