Noonan syndrome

Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.54). 09/2007; 145C(3):274-9. DOI: 10.1002/ajmg.c.30138
Source: PubMed

ABSTRACT Noonan syndrome is a common autosomal dominant condition caused by multiple genes in the RasMAPK pathway. The adult phenotype can be extremely subtle, and many adults are diagnosed only after the birth of a more obviously affected child. Whether diagnosis is made in childhood or adulthood, initial and ongoing evaluation of many systems can have considerable health benefits.

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    ABSTRACT: Congenital heart disease is the most common type of birth defect in the newborn—occurring in 1 % of neonates. In addition, cardiac defects account for nearly half of the neonatal deaths resulting from congenital malformations. Due to recent advances in spatial resolution of ultrasound machines and improvements in sonographic techniques, the clinician is increasingly able to detect cardiac anomalies in utero. At the same time, advances in cardiovascular surgery have improved the overall survival of the affected neonates. Due to the combination of advances in prenatal diagnosis and postnatal intervention, parents with fetuses affected by congenital cardiac defects have become the largest group who seek prenatal counseling on the risks of associated anomalies, risks for subsequent pregnancies, and the risks to the offspring of a successfully treated patient. Although most congenital heart defects are not familiarly clustered, genetic factors are still involved in most cases. In this review, we summarize recent evidence of chromosomal and genetic defects associated with congenital heart diseases to provide the optimal counseling and management for the parents with affected neonates.
    12/2012; 1(4). DOI:10.1007/s13669-012-0021-8
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    ABSTRACT: Neurofibromatosis type 1 (NF1), a genetic disease that affects 1 in 3,000, is caused by loss of a large evolutionary conserved protein that serves as a GTPase Activating Protein (GAP) for Ras. Among Drosophila melanogaster Nf1 (dNf1) null mutant phenotypes, learning/memory deficits and reduced overall growth resemble human NF1 symptoms. These and other dNf1 defects are relatively insensitive to manipulations that reduce Ras signaling strength but are suppressed by increasing signaling through the 3'-5' cyclic adenosine monophosphate (cAMP) dependent Protein Kinase A (PKA) pathway, or phenocopied by inhibiting this pathway. However, whether dNf1 affects cAMP/PKA signaling directly or indirectly remains controversial. To shed light on this issue we screened 486 1(st) and 2(nd) chromosome deficiencies that uncover >80% of annotated genes for dominant modifiers of the dNf1 pupal size defect, identifying responsible genes in crosses with mutant alleles or by tissue-specific RNA interference (RNAi) knockdown. Validating the screen, identified suppressors include the previously implicated dAlk tyrosine kinase, its activating ligand jelly belly (jeb), two other genes involved in Ras/ERK signal transduction and several involved in cAMP/PKA signaling. Novel modifiers that implicate synaptic defects in the dNf1 growth deficiency include the intersectin-related synaptic scaffold protein Dap160 and the cholecystokinin receptor-related CCKLR-17D1 drosulfakinin receptor. Providing mechanistic clues, we show that dAlk, jeb and CCKLR-17D1 are among mutants that also suppress a recently identified dNf1 neuromuscular junction (NMJ) overgrowth phenotype and that manipulations that increase cAMP/PKA signaling in adipokinetic hormone (AKH)-producing cells at the base of the neuroendocrine ring gland restore the dNf1 growth deficiency. Finally, supporting our previous contention that ALK might be a therapeutic target in NF1, we report that human ALK is expressed in cells that give rise to NF1 tumors and that NF1 regulated ALK/RAS/ERK signaling appears conserved in man.
    PLoS Genetics 11/2013; 9(11):e1003958. DOI:10.1371/journal.pgen.1003958 · 8.17 Impact Factor
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    ABSTRACT: Noonan syndrome is an autosomal, dominantly inherited disease; it is physically characterized by short stature, short neck, webbed neck, abnormal auricles, high arched palate, and cardiovascular malformation. Its pathological condition is thought to be due to a gain-of-function mutation in the Ras-mitogen-activated protein kinase (MAPK) signal transduction pathway. Eyelid abnormalities such as ocular hypertelorism and blepharoptosis are the most commonly observed eye complications. We report a case of Noonan syndrome associated with mature cataract that required operation. A 42-year-old man was diagnosed with Noonan syndrome at the age of 1 year. He underwent an eye examination after complaining of decreased visual acuity in the right eye and was diagnosed with mature cataract, which was treated by cataract surgery. There were no intraoperative complications, and the postoperative course was uneventful. Protein analysis of lens capsule and epithelium at capsulorhexis showed MAPK cascade proteins such as ERK and p38MAPK were upregulated. An abnormality in the PTPN11 gene was also observed; a potential mechanism of cataract onset may be that opacity of the lens rapidly progressed due to abnormal activation of the Ras-MAPK signal transduction pathway. This case highlights the possible association of cataract formation with MAPK cascade protein upregulation in Noonan syndrome.
    BMC Ophthalmology 11/2013; 13(1):70. DOI:10.1186/1471-2415-13-70 · 1.08 Impact Factor


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