Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers


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By contrast, the proliferation marker Ki revealed a weak proliferative index in adenomas compared with adenocarcinomas. They concluded that a substantial number of cells in premalignant tumors undergo oncogene-induced senescence, but that cells in malignant tumors are unable to do this owing to the loss of oncogene-induced senescence effectors such as p16 INK4a or p Using an Hras knockin mouse model, To et al. Although the Kras 4A isoform is dispensable for mouse development, it is the most important isoform for lung carcinogenesis in vivo and for the inhibitory effect of wildtype Kras on the mutant allele.

Kras 4A expression is detected in a subpopulation of normal lung epithelial cells, but at very low levels in lung tumors, suggesting that it may not be required for tumor progression. The 2 Kras isoforms undergo different posttranslational modifications.


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To et al. Junttila et al. Surprisingly, p53 restoration failed to induce significant regression of established tumors, although it did result in a significant decrease in the relative proportion of high-grade tumors. This was due to selective activation of p53 only in the more aggressive tumor cells within each tumor. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signaling sensor p19 ARF Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumor evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.

A single endogenous mutant Kras allele is sufficient to promote lung tumor formation in mice, but malignant progression requires additional genetic alterations. Through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, Kerr et al. This metabolic rewiring is recapitulated in mutant KRAS homozygous nonsmall cell lung cancer cells and in vivo, and in spontaneous advanced murine lung tumors which display a high frequency of Kras G12D copy gain , but not in the corresponding early tumors Kras G12D heterozygous. Finally, Kerr et al.

The authors concluded that mutant Kras lung tumors are not a single disease but rather a heterogeneous group comprising 2 classes of tumors with distinct metabolic profiles, prognosis, and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. Studies of the mutant protein showed that it had transforming abilities consistent with activation of the gene.

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In a study of prospectively enrolled patients with primary adenocarcinoma of the lung, Ahrendt et al. Thirty-nine of the 40 tumors with KRAS2 mutations had 1 of 4 changes in codon 12, the most common being G12C, which was present in 25 tumors. In a squamous cell lung carcinoma from a year-old man, Santos et al. The mutation was not identified in the patient's normal bronchial and pulmonary parenchymal tissues or blood lymphocytes.

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This mutation had previously been identified in a bladder cancer and a lung cancer. In a cell line from a human breast adenocarcinoma , Kozma et al. In white blood cells derived from a 7-month-old girl with juvenile myelomonocytic leukemia JMML; , Matsuda et al. The mutation was seen exclusively in the hematopoietic cell line, including granulocytes, monocytes, and lymphocytes.

Takagi et al. In a patient patient 1 with oculoectodermal syndrome OES; , Peacock et al. The mutation was confirmed by both Sanger and next-generation sequencing allelic frequency, The mutation was also detectable in her hyperpigmented skin, periosteum, muscle, and humerus NOF samples allelic frequencies, In a human transitional cell bladder carcinoma cell line , Grimmond et al.

The mutation was present in paraffin-embedded tissue from the primary tumor of the patient. Motojima et al. In 2 of these 46 tumors, the mutations were glyto-asp G12D and glyto-val G12V; Bourdeaut et al. There was also an incidental finding of micropolycystic kidneys without impaired renal function. Both the epidermal nevus and the rhabdomyosarcoma carried the G12D mutation, which was not found in normal dermal tissue, bone, cheek swap, or lymphocytes.

No renal tissue was available for study. The phenotype was consistent with broad activation of the KRAS pathway. Hafner et al. In white blood cells derived from a month-old girl with juvenile myelomonocytic leukemia JMML; , Matsuda et al. For discussion of the glyto-val G12V substitution that was found in 1 of 53 pancreatic carcinomas by Motojima et al.

In white blood cells derived from a 4-month-old girl with juvenile myelomonocytic leukemia JMML; , Matsuda et al. This mutation was the first dominant RAS mutation found in human cancer that did not involve residues 12, 13, or In an individual with cardiofaciocutaneous syndrome CFC2; , Niihori et al. In 2 unrelated individuals with cardiofaciocutaneous syndrome CFC2; , Niihori et al.

The DV mutation was identified in DNA extracted from both blood and buccal cells of 1 of the individuals. This heterozygous mutation and G60R The results suggested that these germline mutations occurred de novo.

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The year-old male had hypertrophic cardiomyopathy, dysplastic mitral valve with prolapse, Noonan-like features, short stature, mild pectus carinatum, unilateral cryptorchidism, mild developmental delay, and grand mal seizures. In a 3-month-old female with Noonan syndrome-3 , Schubbert et al. The child had a severe clinical phenotype and presented with a myeloproliferative disorder of the juvenile myelomonocytic leukemia JMML; type. The mutation was present in the patient's buccal cells but was absent in parental DNA. Clinical features included atrial septal defect, ventricular septal defect, valvular pulmonary stenosis, dysmorphic facial features, short stature, webbed neck, severe developmental delay, macrocephaly, and sagittal suture synostosis.

Kratz et al. The findings indicated that dysregulated RAS signaling may lead to abnormal growth or premature calvarian closure. Each individual showed a mild clinical phenotype, and none had a history of myeloproliferative disorder or cancer. In a year-old female with the diagnosis of cardiofaciocutaneous syndrome CFC2; , Schubbert et al.

The patient had pulmonic stenosis, left ventricular hypertrophy, Noonan-like facial features, short stature, short neck, broad thorax, lymphedema, chylothorax, left ptosis, severe developmental delay, and agenesis of the corpus callosum. In a 1-year-old girl with the diagnosis of Noonan syndrome-3 NS3; , Carta et al. The patient had macrocephaly with high and broad forehead, curly and sparse hair, hypertelorism, strabismus, epicanthic folds, downslanting palpebral fissures, hypoplastic nasal bridge with bulbous tip of the nose, high palate and macroglossia, low-set and posteriorly rotated ears, short neck with redundant skin, wide-set nipples, and umbilical hernia.

She had been born at 32 weeks' gestation by cesarean section after a pregnancy complicated by a cystic hygroma detected at 12 weeks and polyhydramnios at 30 weeks. At birth she showed edema of the lower limbs. The phenotype showed features overlapping Costello syndrome polyhydramnios, neonatal macrosomia, and macrocephaly, loose skin, and severe failure to thrive and, to a lesser extent, CFC syndrome macrocephaly and sparse hair.

The girl had short stature and growth retardation and delayed bone age, cardiac defects moderate ventricular hypertrophy, mild pulmonic stenosis, and atrial septal defect , dysmorphic features hypertelorism, downslanting palpebral fissures, strabismus, low-set and thick ears, relative macrocephaly with high forehead, and a depressed nasal bridge , short and mildly webbed neck, wide-set nipples, and developmental delay.

There was hyperpigmentation of the skin and a large cafe-au-lait spot on the face. Gestation was complicated by polyhydramnios. In 1 of 21 sporadic pilocytic astrocytoma PA see samples, Sharma et al. The tumor arose in the cortex of an year-old boy; the mutation was not identified in the germline of the patient. Immunohistochemical studies showed increased phospho-AKT see activity compared to controls in all 21 PA samples, indicating increased activation of the Ras pathway.

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The patient had hypertelorism, downslanting palpebral fissures, coarse facies, pectus carinatum, sparse hair, redundant skin, and moderate mental retardation. Kerr et al. In a male infant with a clinical diagnosis of Costello syndrome who died suddenly at age 14 months, Zenker et al.

The patient had coarse facies, cardiac defects, sparse hair, loose and redundant skin, developmental delay, and moderate mental retardation. In a year-old woman with clinical features typical of Costello syndrome and additional findings seen in Noonan syndrome NS3; , Bertola et al.

The mutation was not found in her unaffected mother or brother or in controls. Bertola et al. In a patient with Noonan syndrome-3 NS3; and craniosynostosis, Kratz et al. A mutation in this same codon G60R; In a mother and son with variable features of cardiofaciocutaneous syndrome CFC2; , Stark et al.


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The mutation was not found in control individuals and was shown by in vitro studies to increase effector affinity. The son had delayed psychomotor development and a distinctive appearance, including curly hair, absent eyebrows, and broad forehead. Echocardiogram was normal at age 3 years. His mother had a similar physical appearance and also had high-arched palate, myopia, and mitral valve prolapse.

She had attended a school for children with special needs. Both patients showed signs of a peripheral sensorimotor axonal neuropathy, more severe in the mother, who developed Charcot arthropathy of the feet. PMP22 testing in the mother was negative, but an additional cause of the neuropathy could not be excluded. The authors stated that this was the first documented vertically transmitted KRAS mutation. Using in vitro assays and transfected COS-7 cells, Cirstea et al. The mutation did not alter the rate of nucleotide dissociation by KRAS.

In a girl with variable features of cardiofaciocutaneous syndrome CFC2; , Stark et al. Lys is part of a motif involved in the binding network for guanine nucleotides, which determine the activation state of RAS proteins. The patient was 1 of a female dizygotic twin pair; the other twin was unaffected. The patient had a high birth weight, macrocephaly, and abnormal craniofacial features, including proptosis, hypertelorism, downslanting palpebral fissures, low-set ears, and short neck, suggestive of Noonan syndrome.

Reexamination at age 3. She also had hypertrophy of the interventricular myocardial septum, myocardial hypertrophy, and pulmonic stenosis. She had mildly delayed development. K is a conserved amino acid within a motif required for guanine base binding by KRAS. Cells transfected with the mutations showed an increase in active RAS compared to controls, consistent with a gain of function.

In a year-old man with oculoectodermal syndrome OES; , who was one of the original boys patient 2 with OES described by Toriello et al. The mutation was also found in samples from the patient's skin, bone marrow from proximal femur, and peripheral blood allelic frequencies, 4. Patient samples included 39 from a main study group and 33 from an independent validation group. This and the G12V variant This and the G12D variant In lesional tissues from a 6-year-old boy with oculoectodermal syndrome OES; , originally reported by Aslan et al. In 2 unrelated children with oculoectodermal syndrome OES; , Boppudi et al.

Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers
Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers
Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers
Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers
Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers Noonan Syndrome - A Bibliography and Dictionary for Physicians, Patients, and Genome Researchers

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