Noonan Syndrome


Noonan Syndrome is an autosamal dominant multi-system disorder, characterised by facial anomalies, short stature, developmental delay, cardiac abnormalities and other symptoms. The syndrome pre-disposes to myeloproliferative disorders ( mainly chronic myeolomonocytic leukemia / juvenile myelomonocytic leukemia and acute lymphoblastic leukemia), with reports of neuroblastoma, rhabdomyosarcoma and a wide range of other tumors.

Literature Analysis

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  • Childhood Cancer
  • Germ-Line Mutation
  • Missense Mutation
  • Infant
  • Leukemia, Myelomonocytic, Juvenile
  • DNA Sequence Analysis
  • LEOPARD Syndrome
  • Proto-Oncogene Proteins
  • Mutation
  • Genetic Predisposition
  • Retroperitoneal Neoplasms
  • Congenital Heart Defects
  • PTPN11
  • p120 GTPase Activating Protein
  • Autologous Transplantat
  • Neurofibromatosis 1
  • DNA Mutational Analysis
  • Synovitis, Pigmented Villonodular
  • Adolescents
  • Neurofibromatosis
  • NRAS
  • KRAS
  • MAP Kinase Signaling System
  • ras Proteins
  • Protein Tyrosine Phosphatases
  • Intracellular Signaling Peptides and Proteins
  • Phenotype
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Restriction Fragment Length Polymorphism
  • Newborns
  • Costello Syndrome
  • Genes, Dominant
  • Pedigree
  • Noonan Syndrome
  • Acute Lymphocytic Leukaemia
  • Exons
  • Mitogen-Activated Protein Kinases
  • RAS Genes
  • Neurofibromin 1
  • NF1
  • SOS1 Protein
  • Genotype
Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (6)

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PTPN11 12q24 CFC, NS1, SHP2, BPTP3, PTP2C, PTP-1D, SH-PTP2, SH-PTP3 -PTPN11 and Noonan Syndrome
KRAS 12p12.1 NS, NS3, CFC2, KRAS1, KRAS2, RASK2, KI-RAS, C-K-RAS, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B -KRAS mutation in Noonan Syndrome
SOS1 2p21 GF1, HGF, NS4, GGF1, GINGF -SOS1 mutation in Noonan Syndrome
RAF1 3p25 NS5, CRAF, Raf-1, c-Raf, CMD1NN -RAF1 mutation in Noonan Syndrome
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS mutation Noonan Syndrome
CBL 11q23.3 CBL2, NSLL, C-CBL, RNF55, FRA11B -CBL mutation in Noonan Syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Noonan Syndrome and cancer:
Cavé H, Caye A, Strullu M, et al.
Acute lymphoblastic leukemia in the context of RASopathies.
Eur J Med Genet. 2016; 59(3):173-8 [PubMed] Related Publications
Noonan syndrome is associated with a range of malignancies including acute lymphoblastic leukemia (ALL). However, little information is available regarding the frequency, natural history, characteristics and prognosis of ALL in Noonan syndrome or RASopathies in general. Cross-referencing data from a large prospective cohort of 1176 patients having a molecularly confirmed RASopathy with data from the French childhood cancer registry allowed us to identify ALL in 6 (0.5%) patients including 4/778 (0.5%) with a germline PTPN11 mutation and 2/94 (2.1%) with a germline SOS1 mutation. None of the patients of our series with CFC syndrome (with germline BRAF or MAP2K1/MAP2K2 mutation - n = 121) or Costello syndrome (with HRAS mutation - n = 35) had an ALL. A total of 19 Noonan-ALL were gathered by adding our patients to those of the International Berlin-Munster-Frankfurt (I-BFM) study group and previously reported patients. Strikingly, all Noonan-associated ALL were B-cell precursor ALL, and high hyperdiploidy with more than 50 chromosomes was found in the leukemia cells of 13/17 (76%) patients with available genetics data. Our data suggest that children with Noonan syndrome are at higher risk to develop ALL. Like what is observed for somatic PTPN11 mutations, NS is preferentially associated with the development of hyperdiploid ALL that will usually respond well to chemotherapy. However, Noonan syndrome patients seem to have a propensity to develop post therapy myelodysplasia that can eventually be fatal. Hence, one should be particularly cautious when treating these patients.

Vurallı D, Gönç N, Vidaud D, et al.
Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.
J Clin Res Pediatr Endocrinol. 2016; 8(1):96-100 [PubMed] Free Access to Full Article Related Publications
Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD.

Ekvall S, Wilbe M, Dahlgren J, et al.
Mutation in NRAS in familial Noonan syndrome--case report and review of the literature.
BMC Med Genet. 2015; 16:95 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Noonan syndrome (NS), a heterogeneous developmental disorder associated with variable clinical expression including short stature, congenital heart defect, unusual pectus deformity and typical facial features, is caused by activating mutations in genes involved in the RAS-MAPK signaling pathway.
CASE PRESENTATION: Here, we present a clinical and molecular characterization of a small family with Noonan syndrome. Comprehensive mutation analysis of NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS was performed using targeted next-generation sequencing. The result revealed a recurrent mutation in NRAS, c.179G > A (p.G60E), in the index patient. This mutation was inherited from the index patient's father, who also showed signs of NS.
CONCLUSIONS: We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS. Neither of affected individuals in this family presented with juvenile myelomonocytic leukemia (JMML), which together with previously published results suggest that the risk for NS individuals with a germline NRAS mutation developing JMML is not different from the proportion seen in other NS cases. Interestingly, 50% of NS individuals with an NRAS mutation (including our family) present with lentigines and/or Café-au-lait spots. This demonstrates a predisposition to hyperpigmented lesions in NRAS-positive NS individuals. In addition, the affected father in our family presented with a hearing deficit since birth, which together with lentigines are two characteristics of NS with multiple lentigines (previously LEOPARD syndrome), supporting the difficulties in diagnosing individuals with RASopathies correctly. The clinical and genetic heterogeneity observed in RASopathies is a challenge for genetic testing. However, next-generation sequencing technology, which allows screening of a large number of genes simultaneously, will facilitate an early and accurate diagnosis of patients with RASopathies.

McWilliams GD, SantaCruz K, Hart B, Clericuzio C
Occurrence of DNET and other brain tumors in Noonan syndrome warrants caution with growth hormone therapy.
Am J Med Genet A. 2016; 170A(1):195-201 [PubMed] Related Publications
Noonan syndrome (NS) is an autosomal dominant developmental disorder caused by mutations in the RAS-MAPK signaling pathway that is well known for its relationship with oncogenesis. An 8.1-fold increased risk of cancer in Noonan syndrome has been reported, including childhood leukemia and solid tumors. The same study found a patient with a dysembryoplastic neuroepithelial tumor (DNET) and suggested that DNET tumors are associated with NS. Herein we report an 8-year-old boy with genetically confirmed NS and a DNET. Literature review identified eight other reports, supporting the association between NS and DNETs. The review also ascertained 13 non-DNET brain tumors in individuals with NS, bringing to 22 the total number of NS patients with brain tumors. Tumor growth while receiving growth hormone (GH) occurred in our patient and one other patient. It is unknown whether the development or progression of tumors is augmented by GH therapy, however there is concern based on epidemiological, animal and in vitro studies. This issue was addressed in a 2015 Pediatric Endocrine Society report noting there is not enough data available to assess the safety of GH therapy in children with neoplasia-predisposition syndromes. The authors recommend that GH use in children with such disorders, including NS, be undertaken with appropriate surveillance for malignancies. Our case report and literature review underscore the association of NS with CNS tumors, particularly DNET, and call attention to the recommendation that clinicians treating NS patients with GH do so with awareness of the possibility of increased neoplasia risk.

Conboy E, Dhamija R, Wang M, et al.
Paraspinal neurofibromas and hypertrophic neuropathy in Noonan syndrome with multiple lentigines.
J Med Genet. 2016; 53(2):123-6 [PubMed] Related Publications
BACKGROUND: Noonan syndrome with multiple lentigines (NSML), formerly known as LEOPARD syndrome, is an autosomal-dominant disorder characterised by lentigines, EKG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, growth retardation and deafness. There is significant clinical overlap between NSML and other disorders that result from dysregulated rat sarcoma/mitogen-activated protein kinase pathway (RASopathies). Except for neurofibromatosis type 1, other RASopathies are not known to be typically associated with neurogenic tumours.
METHODS AND RESULTS: We evaluated patients from three families with pigmentary skin lesions, progressive neuropathy, enlarged nerves, massive burden of paraspinal tumours (neurofibroma was confirmed in one patient) and a clinical diagnosis of NSML. All patients had a mutation in the protein tyrosine phosphatase catalytic domain of the PTPN11 gene; two unrelated patients had the p.Thr468Met mutation, while the family consisting of two affected individuals harboured the p.Thr279Cys mutation. Molecular analysis performed on hypertrophic nerve tissue did not disclose a second somatic hit in NF1, PTPN11, NF2 or SMARCB1 genes.
CONCLUSIONS: Neurogenic tumours and hypertrophic neuropathy are unusual complications of NSML and may be an under-recognised manifestation that would warrant surveillance. Our observation may also have implications for other disorders caused by RAS-pathway dysregulation.

Garavelli L, Cordeddu V, Errico S, et al.
Noonan syndrome-like disorder with loose anagen hair: a second case with neuroblastoma.
Am J Med Genet A. 2015; 167A(8):1902-7 [PubMed] Related Publications
Noonan-like syndrome with loose anagen hair (NSLH), also known as Mazzanti syndrome, is a RASopathy characterized by craniofacial features resembling Noonan syndrome, cardiac defects, cognitive deficits and behavioral issues, reduced growth generally associated with GH deficit, darkly pigmented skin, and an unique combination of ectodermal anomalies. Virtually all cases of NSLH are caused by an invariant and functionally unique mutation in SHOC2 (c.4A>G, p.Ser2Gly). Here, we report on a child with molecularly confirmed NSLH who developed a neuroblastoma, first suspected at the age 3 months by abdominal ultrasound examination. Based on this finding, scanning of the SHOC2 coding sequence encompassing the c.4A>G change was performed on selected pediatric cohorts of malignancies documented to occur in RASopathies (i.e., neuroblastoma, brain tumors, rhabdomyosarcoma, acute lymphoblastic, and myeloid leukemia), but failed to identify a functionally relevant cancer-associated variant. While these results do not support a major role of somatic SHOC2 mutations in these pediatric cancers, this second instance of neuroblastoma in NSLAH suggests a possible predisposition to this malignancy in subjects heterozygous for the c.4A>G SHOC2 mutation.

Kratz CP, Franke L, Peters H, et al.
Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes.
Br J Cancer. 2015; 112(8):1392-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Somatic mutations affecting components of the Ras-MAPK pathway are a common feature of cancer, whereas germline Ras pathway mutations cause developmental disorders including Noonan, Costello, and cardio-facio-cutaneous syndromes. These 'RASopathies' also represent cancer-prone syndromes, but the quantitative cancer risks remain unknown.
METHODS: We investigated the occurrence of childhood cancer including benign and malignant tumours of the central nervous system in a group of 735 individuals with germline mutations in Ras signalling pathway genes by matching their information with the German Childhood Cancer Registry.
RESULTS: We observed 12 cases of cancer in the entire RASopathy cohort vs 1.12 expected (based on German population-based incidence rates). This corresponds to a 10.5-fold increased risk of all childhood cancers combined (standardised incidence ratio (SIR)=10.5, 95% confidence interval=5.4-18.3). The specific cancers included juvenile myelomonocytic leukaemia=4; brain tumour=3; acute lymphoblastic leukaemia=2; rhabdomyosarcoma=2; and neuroblastoma=1. The childhood cancer SIR in Noonan syndrome patients was 8.1, whereas that for Costello syndrome patients was 42.4.
CONCLUSIONS: These data comprise the first quantitative evidence documenting that the germline mutations in Ras signalling pathway genes are associated with increased risks of both childhood leukaemia and solid tumours.

Nair S, Fort JA, Yachnis AT, Williams CA
Optic nerve pilomyxoid astrocytoma in a patient with Noonan syndrome.
Pediatr Blood Cancer. 2015; 62(6):1084-6 [PubMed] Related Publications
Noonan syndrome (NS; MIM 163950) is an autosomal dominant syndrome which is clinically diagnosed by the distinct facial features, short stature, cardiac anomalies and developmental delay. About 50% of cases are associated with gain of function mutations in PTPN11 gene which leads to activation of the RAS/mitogen-activated protein kinase signaling pathway. This is known to have a role in tumorigenesis. Despite this, only limited reports of solid tumors (Fryssira H, Leventopoulos G, Psoni S, et al. Tumor development in three patients with Noonan syndrome. Eur J Pediatr 2008;167:1025-1031; Schuettpelz LG, McDonald S, Whitesell K et al. Pilocytic astrocytoma in a child with Noonan syndrome. Pediatr Blood Cancer 2009;53:1147-1149; Sherman CB, Ali-Nazir A, Gonzales-Gomez I, et al. Primary mixed glioneuronal tumor of the central nervous system in a patient with Noonan syndrome. J Pediatr Hematol Oncol 2009;31:61-64; Sanford RA, Bowman R, Tomita T, et al. A 16 year old male with Noonan's syndrome develops progressive scoliosis and deteriorating gait. Pediatr Neurosurg 1999;30:47-52) and no prior reports of optic gliomas have been described in patients with NS. We present here a patient with NS with a PTPN11 mutation and an optic pathway pilomyxoid astrocytoma.

Kanakatti Shankar R, Inge TH, Gutmark-Little I, Backeljauw PF
Oophorectomy versus salpingo-oophorectomy in Turner syndrome patients with Y-chromosome material: clinical experience and current practice patterns assessment.
J Pediatr Surg. 2014; 49(11):1585-8 [PubMed] Related Publications
BACKGROUND/PURPOSE: Gonadectomy is recommended in Turner syndrome (TS) patients with Y-chromosome material due to high risk of tumor in the dysgenetic gonads. No recommendations exist on whether concurrent salpingectomy should be performed.
METHODS: A retrospective chart review of surgical procedure and histopathology in TS patients with Y-chromosome enrolled in a TS database was undertaken at Cincinnati Children's Hospital Medical Center. An electronic survey was sent to members of the International Pediatric Endosurgery Group to assess prevalent practice patterns and attitudes on gonadectomy and concurrent salpingectomy in this population.
RESULTS: In March 2011, 12/158 (8%) TS girls (mean age 6.6 years) enrolled in the database had TS with Y-chromosome. Gonadoblastoma was identified in 4/12 (33%) patients and 2/4 had malignant transformation to dysgerminoma and teratoma. Approach to gonadectomy was varied and 3/12 had concurrent salpingectomy. Fifty-four laparoscopic surgeons responded to the survey with no clear consensus on whether salpingectomy should be concurrently performed.
CONCLUSIONS: TS patients with Y-chromosome have an increased risk of gonadal tumor development and gonadectomy is recommended. While there is no consensus among pediatric laparoscopic surgeons on concurrent salpingectomy, it is reasonable to consider this combination procedure.

Pinna V, Lanari V, Daniele P, et al.
p.Arg1809Cys substitution in neurofibromin is associated with a distinctive NF1 phenotype without neurofibromas.
Eur J Hum Genet. 2015; 23(8):1068-71 [PubMed] Free Access to Full Article Related Publications
Analysis of 786 NF1 mutation-positive subjects with clinical diagnosis of neurofibromatosis type 1 (NF1) allowed to identify the heterozygous c.5425C>T missense variant (p.Arg1809Cys) in six (0.7%) unrelated probands (three familial and three sporadic cases), all exhibiting a mild form of disease. Detailed clinical characterization of these subjects and other eight affected relatives showed that all individuals had multiple cafè-au-lait spots, frequently associated with skinfold freckling, but absence of discrete cutaneous or plexiform neurofibromas, Lisch nodules, typical NF1 osseous lesions or symptomatic optic gliomas. Facial features in half of the individuals were suggestive of Noonan syndrome. Our finding and revision of the literature consistently indicate that the c.5425C>T change is associated with a distinctive, mild form of NF1, providing new data with direct impact on genetic counseling and patient management.

Hernández-Porras I, Fabbiano S, Schuhmacher AJ, et al.
K-RasV14I recapitulates Noonan syndrome in mice.
Proc Natl Acad Sci U S A. 2014; 111(46):16395-400 [PubMed] Free Access to Full Article Related Publications
Noonan syndrome (NS) is an autosomal dominant genetic disorder characterized by short stature, craniofacial dysmorphism, and congenital heart defects. NS also is associated with a risk for developing myeloproliferative disorders (MPD), including juvenile myelomonocytic leukemia (JMML). Mutations responsible for NS occur in at least 11 different loci including KRAS. Here we describe a mouse model for NS induced by K-Ras(V14I), a recurrent KRAS mutation in NS patients. K-Ras(V14I)-mutant mice displayed multiple NS-associated developmental defects such as growth delay, craniofacial dysmorphia, cardiac defects, and hematologic abnormalities including a severe form of MPD that resembles human JMML. Homozygous animals had perinatal lethality whose penetrance varied with genetic background. Exposure of pregnant mothers to a MEK inhibitor rescued perinatal lethality and prevented craniofacial dysmorphia and cardiac defects. However, Mek inhibition was not sufficient to correct these defects when mice were treated after weaning. Interestingly, Mek inhibition did not correct the neoplastic MPD characteristic of these mutant mice, regardless of the timing at which the mice were treated, thus suggesting that MPD is driven by additional signaling pathways. These genetically engineered K-Ras(V14I)-mutant mice offer an experimental tool for studying the molecular mechanisms underlying the clinical manifestations of NS. Perhaps more importantly, they should be useful as a preclinical model to test new therapies aimed at preventing or ameliorating those deficits associated with this syndrome.

Knauer-Fischer S, Besikoglu B, Inta I, et al.
Analyses of Gonadoblastoma Y (GBY)-locus and of Y centromere in Turner syndrome patients.
Exp Clin Endocrinol Diabetes. 2015; 123(1):61-5 [PubMed] Related Publications
BACKGROUND: Mosaicism with cytogenetically visible Y chromosome is found in 5-6% of Turner Syndrome (TS) patients. Additionally, occult Y-chromosome derived material is increasingly found in patients with monosomy X when using more sensitive molecular techniques. These TS patients are at risk of developing gonadoblastomas when the Y genes presumed to be involved in gonadoblastoma development (Gonadoblastoma-Y-locus; GBY) are present.
AIM: To find occult Y-chromosome material in TS patients and to correlate the patient's phenotype to Y-chromosome material.
METHODS: We studied 60 TS-patients for presence of the Y chromosome with focus on the Gonadoblastoma Y-locus and its extension in Yp and Yq using sensitive Y centromere and Y gene deletion PCR assays. In addition, we evaluated their individual clinical and auxological characteristics.
RESULTS: We identified presence of the GBY-locus in 7 patients (11.7%) including 4 patients without evidence for a Y chromosome in their preceding standard karyotype analyses. Clinical and auxological characteristics were similar in GBY-positive and GBY-negative patients.
CONCLUSIONS: Presence of the GBY locus in Turner patients with no indication of the Y chromosome in standard cytogenetic chromosome analysis can be revealed by sensitive molecular PCR assays screening for presence of the Y centromere and the GBY-candidate-genes in proximal Yp11 and Yq11, respectively.

Hyakuna N, Muramatsu H, Higa T, et al.
Germline mutation of CBL is associated with moyamoya disease in a child with juvenile myelomonocytic leukemia and Noonan syndrome-like disorder.
Pediatr Blood Cancer. 2015; 62(3):542-4 [PubMed] Related Publications
Germline mutations in CBL have been identified in patients with Noonan syndrome-like phenotypes, while juvenile myelomonocytic leukemia (JMML) harbors duplication of a germline CBL, resulting in acquired isodisomy. The association between moyamoya disease and Noonan syndrome carrying a PTPN11 mutation has recently been reported. We present a patient with JMML who developed moyamoya disease and neovascular glaucoma. Our patient exhibited a Noonan syndrome-like phenotype. Genetic analysis revealed acquired isodisomy and a germline heterozygous mutation in CBL. This is a rare case of CBL mutation associated with moyamoya disease. Prolonged RAS pathway signaling may cause disruption of cerebrovascular development.

Bezniakow N, Gos M, Obersztyn E
The RASopathies as an example of RAS/MAPK pathway disturbances - clinical presentation and molecular pathogenesis of selected syndromes.
Dev Period Med. 2014 Jul-Sep; 18(3):285-96 [PubMed] Related Publications
The RASopathies are a class of developmental syndromes. Each of them exhibits distinctive phenotypic features, although there are numerous overlapping clinical manifestations that include: dysmorphic craniofacial features, congenital cardiac defects, skin abnormalities, varying degrees of intellectual disability and increased risk of malignancies. These disorders include: Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Legius syndrome and neurofibromatosis type 1 (NF1). The RASopathies are associated with the presence of germline mutation in genes encoding specific proteins of the RAS/mitogen - activated protein kinase (MAPK) pathway that plays a crucial role in embryonic and postnatal development. In this review, we present the clinical and molecular features of selected syndromes from the RASopathies group.

Strullu M, Caye A, Lachenaud J, et al.
Juvenile myelomonocytic leukaemia and Noonan syndrome.
J Med Genet. 2014; 51(10):689-97 [PubMed] Related Publications
BACKGROUND: Infants with Noonan syndrome (NS) are predisposed to developing juvenile myelomonocytic leukaemia (JMML) or JMML-like myeloproliferative disorders (MPD). Whereas sporadic JMML is known to be aggressive, JMML occurring in patients with NS is often considered as benign and transitory. However, little information is available regarding the occurrence and characteristics of JMML in NS.
METHODS AND RESULTS: Within a large prospective cohort of 641 patients with a germline PTPN11 mutation, we identified MPD features in 36 (5.6%) patients, including 20 patients (3%) who fully met the consensus diagnostic criteria for JMML. Sixty percent of the latter (12/20) had severe neonatal manifestations, and 10/20 died in the first month of life. Almost all (11/12) patients with severe neonatal JMML were males. Two females who survived MPD/JMML subsequently developed another malignancy during childhood. Although the risk of developing MPD/JMML could not be fully predicted by the underlying PTPN11 mutation, some germline PTPN11 mutations were preferentially associated with myeloproliferation: 10/48 patients with NS (20.8%) with a mutation in codon Asp61 developed MPD/JMML in infancy. Patients with a p.Thr73Ile mutation also had more chances of developing MPD/JMML but with a milder clinical course. SNP array and whole exome sequencing in paired tumoral and constitutional samples identified no second acquired somatic mutation to explain the occurrence of myeloproliferation.
CONCLUSIONS: JMML represents the first cause of death in PTPN11-associated NS. Few patients have been reported so far, suggesting that JMML may sometimes be overlooked due to early death, comorbidities or lack of confirmatory tests.

Huang WQ, Lin Q, Zhuang X, et al.
Structure, function, and pathogenesis of SHP2 in developmental disorders and tumorigenesis.
Curr Cancer Drug Targets. 2014; 14(6):567-88 [PubMed] Related Publications
Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the human PTPN11 gene, is a ubiquitously expressed protein tyrosine phosphatase (PTP) that consists of two tandem Src homology (SH2) domains (N-SH2 and C-SH2), a PTP catalytic domain, and a C-terminal tail with tyrosyl phosphorylation sites. It plays critical roles in numerous cellular processes through the regulation of various signaling pathways in PTP catalytic activity-dependent and -independent manners. Dysfunction of SHP2 resulting from pathogenic mutations and aberrant expression leads to the dysregulation of multiple signaling pathways, thus contributing to different human disorders. Germline and somatic mutations in PTPN11 are involved in Noonan syndrome (NS), LEOPARD syndrome (LS), and hematological malignancies, as well as several solid tumors. In this report, we provide an overview of the current knowledge of the structure and function of SHP2, and further discuss the molecular and pathogenic mechanism of SHP2 in human diseases, with a special focus on tumorigenesis. Furthermore, we summarize that SHP2 might itself represent a potential drug target for cancer prevention and treatment. Ongoing research and development of SHP2-specific inhibitors would enhance this potential.

Pootrakul L, Nazareth MR, Cheney RT, Grassi MA
Lymphangioma circumscriptum of the vulva in a patient with Noonan syndrome.
Cutis. 2014; 93(6):297-300 [PubMed] Related Publications
Lymphangioma circumscriptum (LC) results from the development of abnormal lymphatic vasculature and is characterized by the presence of grouped vesicles filled with clear or colored fluid. Vulvar localization is uncommon. Abnormalities of the lymphatic system, such as lymphedema and cystic hygroma, are well-known features of genetic disorders such as Noonan syndrome (NS) and Turner syndrome. We report the case of a patient with NS who presented with LC of the vulva. We also discuss the expanding spectrum of clinical anomalies associated with the presentation of NS.

Santoro C, Pacileo G, Limongelli G, et al.
LEOPARD syndrome: clinical dilemmas in differential diagnosis of RASopathies.
BMC Med Genet. 2014; 15:44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Diagnosis within RASopathies still represents a challenge. Nevertheless, many efforts have been made by clinicians to identify specific clinical features which might help in differentiating one disorder from another. Here, we describe a child initially diagnosed with Neurofibromatosis-Noonan syndrome. The follow-up of the proband, the clinical evaluation of his father together with a gene-by-gene testing approach led us to the proper diagnosis.
CASE PRESENTATION: We report a 8-year-old male with multiple café-au-lait macules, several lentigines and dysmorphic features that suggest Noonan syndrome initially diagnosed with Neurofibromatosis-Noonan syndrome. However, after a few years of clinical and ophthalmological follow-up, the absence of typical features of Neurofibromatosis type 1 and the lack of NF1 mutation led us to reconsider the original diagnosis. A new examination of the patient and his similarly affected father, who was initially referred as healthy, led us to suspect LEOPARD syndrome, The diagnosis was then confirmed by the occurrence in both patients of a heterozygous mutation c.1403 C > T, p.(Thr468Met), of PTPN11. Subsequently, the proband was also found to have type-1 Arnold-Chiari malformation in association with syringomyelia.
CONCLUSION: Our experience suggests that differential clinical diagnosis among RASopathies remains ambiguous and raises doubts on the current diagnostic clinical criteria. In some cases, genetic tests represent the only conclusive proof for a correct diagnosis and, consequently, for establishing individual prognosis and providing adequate follow-up. Thus, molecular testing represents an essential tool in differential diagnosis of RASophaties. This view is further strengthened by the increasing accessibility of new sequencing techniques.Finally, to our knowledge, the described case represents the third report of the occurrence of Arnold Chiari malformation and the second description of syringomyelia with LEOPARD syndrome.

Ahmed B, Amin M
Postpubertal cherubism with Noonan syndrome.
J Coll Physicians Surg Pak. 2014; 24 Suppl 1:S39-40 [PubMed] Related Publications
Cherubism is a self limiting, autosomal dominant, fibro-osseous lesion of the maxillo facial region affecting the young adults. The etiology is considered to be a mutation of the SH3BP2 gene from chromosome 4p16.3. Sporadic non-familial cases have also been reported. The affected subjects usually present with simultaneous, bilateral swellings of the maxillae and/or mandible, premature loss of primary teeth, malocclusion due to disturbed eruption pattern of permanent teeth and a characteristic chubby faced angelic eyed appearance. This usually presents as an isolated finding, however, it can exist in association with syndromes like Noonan's syndrome, Jaffe syndrome, Gardener syndrome and Ollier's disease. Treatment is focused on the exact genetic diagnosis and management of symptomatic conditions utilizing cosmetic surgery and orthodontics. Genetic counselling of the affected families may help to decrease its incidence. This report presents a rare case of cherubism with associated features of Noonan syndrome.

Flex E, Jaiswal M, Pantaleoni F, et al.
Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.
Hum Mol Genet. 2014; 23(16):4315-27 [PubMed] Free Access to Full Article Related Publications
RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.

Ekvall S, Sjörs K, Jonzon A, et al.
Novel association of neurofibromatosis type 1-causing mutations in families with neurofibromatosis-Noonan syndrome.
Am J Med Genet A. 2014; 164A(3):579-87 [PubMed] Related Publications
Neurofibromatosis-Noonan syndrome (NFNS) is a rare condition with clinical features of both neurofibromatosis type 1 (NF1) and Noonan syndrome (NS). All three syndromes belong to the RASopathies, which are caused by dysregulation of the RAS-MAPK pathway. The major gene involved in NFNS is NF1, but co-occurring NF1 and PTPN11 mutations in NFNS have been reported. Knowledge about possible involvement of additional RASopathy-associated genes in NFNS is, however, very limited. We present a comprehensive clinical and molecular analysis of eight affected individuals from three unrelated families displaying features of NF1 and NFNS. The genetic etiology of the clinical phenotypes was investigated by mutation analysis, including NF1, PTPN11, SOS1, KRAS, NRAS, BRAF, RAF1, SHOC2, SPRED1, MAP2K1, MAP2K2, and CBL. All three families harbored a heterozygous NF1 variant, where the first family had a missense variant, c.5425C>T;p.R1809C, the second family a recurrent 4bp-deletion, c.6789_6792delTTAC;p.Y2264Tfs*6, and the third family a splice-site variant, c.2991-1G>A, resulting in skipping of exon 18 and an in-frame deletion of 41 amino acids. These NF1 variants have all previously been reported in NF1 patients. Surprisingly, both c.6789_6792delTTAC and c.2991-1G>A are frequently associated with NF1, but association to NFNS has, to our knowledge, not previously been reported. Our results support the notion that NFNS represents a variant of NF1, genetically distinct from NS, and is caused by mutations in NF1, some of which also cause classical NF1. Due to phenotypic overlap between NFNS and NS, we propose screening for NF1 mutations in NS patients, preferentially when café-au-lait spots are present.

Cizmarova M, Kostalova L, Pribilincova Z, et al.
Rasopathies - dysmorphic syndromes with short stature and risk of malignancy.
Endocr Regul. 2013; 47(4):217-22 [PubMed] Related Publications
OBJECTIVES: The term ´Rasopathies´ represents a group of five neurodevelopmental syndromes (Noonan, LEOPARD, Costello, Cardio-facio-cutaneous, and Neurofibromatose-Noonan syndrome) caused by germline mutation in genes encoding proteins involved in RAS/MAPK (rat sarcoma/mitogen-activated protein kinase) signaling pathway. The RAS/MAPK signaling pathway participates in regulation of cell determination, proliferation, differentiation, migration, and senescence and dysregulation of this pathway can lead to the risk of tumorigenesis. In this review, we aim to summarize the current clinical and molecular genetic knowledge on Rasopathies with special attention for the risk of cancer. We propose also clinical and therapeutic approach for patients with malignancy.
METHODS: We are reviewing the clinical and molecular basis of Rasopathies based on recent studies, clinical examination, and molecular diagnostics (mutation analysis of causal genes for Rasopathies) in Slovak pediatric patients.
RESULTS: Some clinical features, such as short stature, a specific facial dysmorphology and cardiac abnormalities are common to all of Rasopathy syndromes. However, there are unique signs by which the syndromes can differ from each other, especially multiple lentigo in LEOPARD syndrome, increased risk of malignancy in Costello syndrome, dry hyperkeratotic skin in patients with cardio-facio-cutaneous syndrome, and neurofibromas and cafe-au-lait spots in neurofibromatosis-Noonan syndrome.
CONCLUSION: Despite the overlapping clinical features, Rasopathy syndromes exhibit unique fenotypical features and the precise molecular diagnostics may lead to confirmation of each syndrome. The molecular diagnostics may allow the detection of pathogenic mutation associated with tumorigenesis.

Sakamoto K, Imamura T, Asai D, et al.
Acute lymphoblastic leukemia developing in a patient with Noonan syndrome harboring a PTPN11 germline mutation.
J Pediatr Hematol Oncol. 2014; 36(2):e136-9 [PubMed] Related Publications
Noonan syndrome (NS) is a congenital genetic disorder characterized by certain facial features, short stature, and congenital heart disease. The disorder is caused by genetic alterations in the RAS/MAPK signal pathway. NS patients show a predisposition to malignancy; however, acute lymphoblastic leukemia (ALL) is rarely reported. Here, we describe a NS patient with B-cell precursor ALL (BCP-ALL) harboring a hyperdiploid karyotype and a PTPN11 germline mutation (c.922A>G; p.N308D). We also discuss the relationship between the hyperdiploid karyotype and genetic alterations in the RAS/MAPK pathway in BCP-ALL.

Yu B, Liu W, Yu WM, et al.
Targeting protein tyrosine phosphatase SHP2 for the treatment of PTPN11-associated malignancies.
Mol Cancer Ther. 2013; 12(9):1738-48 [PubMed] Free Access to Full Article Related Publications
Activating mutations in PTPN11 (encoding SHP2), a protein tyrosine phosphatase (PTP) that plays an overall positive role in growth factor and cytokine signaling, are directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Identification of SHP2-selective inhibitors could lead to the development of new drugs that ultimately serve as treatments for PTPN11-associated diseases. As the catalytic core of SHP2 shares extremely high homology to those of SHP1 and other PTPs that play negative roles in cell signaling, to identify selective inhibitors of SHP2 using computer-aided drug design, we targeted a protein surface pocket that is adjacent to the catalytic site, is predicted to be important for binding to phosphopeptide substrates, and has structural features unique to SHP2. From computationally selected candidate compounds, #220-324 effectively inhibited SHP2 activity with an IC50 of 14 μmol/L. Fluorescence titration experiments confirmed its direct binding to SHP2. This active compound was further verified for its ability to inhibit SHP2-mediated cell signaling and cellular function with minimal off-target effects. Furthermore, mouse myeloid progenitors with the activating mutation (E76K) in PTPN11 and patient leukemic cells with the same mutation were more sensitive to this inhibitor than wild-type cells. This study provides evidence that SHP2 is a "druggable" target for the treatment of PTPN11-associated diseases. As the small-molecule SHP2 inhibitor identified has a simple chemical structure, it represents an ideal lead compound for the development of novel anti-SHP2 drugs. Mol Cancer Ther; 12(9); 1738-48. ©2013 AACR.

Timeus F, Crescenzio N, Baldassarre G, et al.
Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome.
Oncol Rep. 2013; 30(2):553-9 [PubMed] Free Access to Full Article Related Publications
Noonan syndrome (NS) is an autosomal dominant disorder, characterized by short stature, multiple dysmorphisms and congenital heart defects. A myeloproliferative disorder (NS/MPD), resembling juvenile myelomonocytic leukemia (JMML), is occasionally diagnosed in infants with NS. In the present study, we performed a functional evaluation of the circulating hematopoietic progenitors in a series of NS, NS/MPD and JMML patients. The different functional patterns were compared with the aim to identify a possible NS subgroup worthy of stringent hematological follow-up for an increased risk of MPD development. We studied 27 NS and 5 JMML patients fulfilling EWOG-MDS criteria. The more frequent molecular defects observed in NS were mutations in the PTPN11 and SOS genes. The absolute count of monocytes, circulating CD34+ hematopoietic progenitors, their apoptotic rate and the number of circulating CFU-GMs cultured in the presence of decreasing concentrations or in the absence of granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated. All JMML patients showed monocytosis>1,000/µl. Ten out of the 27 NS patients showed monocytosis>1,000/µl, which included the 3 NS/MPD patients. In JMML patients, circulating CD34+ cells were significantly increased (median, 109.8/µl; range, 44-232) with a low rate of apoptosis (median, 2.1%; range, 0.4-12.1%), and circulating CFU-GMs were hyper-responsive to GM-CSF. NS/MPD patients showed the same flow cytometric pattern as the JMML patients (median, CD34+ cells/µl, 205.7; range, 58-1374; median apoptotic rate, 1.4%; range, 0.2-2.4%) and their circulating CFU-GMs were hyper-responsive to GM-CSF. These functional alterations appeared 10 months before the typical clinical manifestations in 1 NS/MPD patient. In NS, the CD34+ absolute cell count and circulating CFU-GMs showed a normal pattern (median CD34+ cells/µl, 4.9; range, 1.3-17.5), whereas the CD34+ cell apoptotic rate was significantly decreased in comparison with the controls (median, 8.6%; range, 0-27.7% vs. median, 17.6%; range, 2.8-49.6%), suggesting an increased CD34+ cell survival. The functional evaluation of circulating hematopoietic progenitors showed specific patterns in NS and NS/MPD. These tests are a reliable integrative tool that, together with clinical data and other hematological parameters, could help detect NS patients with a high risk for a myeloproliferative evolution.

Eckmann-Scholz C, Salmassi A, Jonat W, Alkatout I
Distended jugular lymphatic sacs in fetuses with increased nuchal translucency: correlation with first-trimester findings in aberrant karyotypes.
J Matern Fetal Neonatal Med. 2014; 27(3):257-60 [PubMed] Related Publications
OBJECTIVE: We investigated the prognostic relevance of ultrasound visibility of distendend jugular lymphatic sacs (JLS) in fetuses with aberrant karyotypes in First-trimester-screening. Furthermore we tried to differentiate between increased nuchal translucency (NT) and cystic hygroma colli.
METHODS: We performed a retrospective single center study in 1874 patients presenting for First-trimester-screening between 2009 and 2013. All fetuses with an abnormal risk calculation and NT > 2.5 mm (95th percentile) were reviewed for ultrasound visibility of JLS. A group of 30 fetuses with normal risk calculation served as control. Karyotyping was performed by chorionic-villi-sampling or amniocentesis, respectively.
RESULTS: In a total of 2030 fetuses 70 (3.44%) with pathologic first-trimester-screening results showed either aberrant karyotypes or severe ultrasound pathologies. Main aberrant karyotypes were trisomy 21 (25), trisomy 18 (16), trisomy 13(six), Monosomy X (four), 47, XYY or 47, XXX (three) and Noonan' syndrome (two). Distended JLS were visible in 47% of all cases. Statistical anaylsis found a significant correlation between NT and JLS size for the fetuses with trisomies 21, 18 and 13 (r = 0.53, p < 0.002). Cystic hygroma colli was present in all Turner and Noonan syndromes.
CONCLUSIONS: Distended JLS have a strong correlation with abnormal karyotypes and increased nuchal translucency. Karyotyping should be offered in these cases.

Cianci P, Tono V, Sala A, et al.
A boy with Burkitt lymphoma associated with Noonan syndrome due to a mutation in RAF1.
Am J Med Genet A. 2013; 161A(6):1401-4 [PubMed] Related Publications
This article reports on an association between Burkitt lymphoma and Noonan syndrome (NS) due to a RAF1 gene mutation. The patient was a 7-year-old boy with NS, who was included in the first series reporting the association between Noonan and RAF1, and who later presented with a 2-week history of asymptomatic unilateral tonsillar swelling and ipsilateral cervical lymphadenopathy. Histological and biological examinations of the tonsillar biopsy led to the diagnosis of Burkitt lymphoma. While there is a well-established association between NS and solid cell tumors, this is the first case described in the literature of Burkitt lymphoma in a patient with NS, and adds to the growing list of data supporting neoplasia's association with NS.

Müller PJ, Rigbolt KT, Paterok D, et al.
Protein tyrosine phosphatase SHP2/PTPN11 mistargeting as a consequence of SH2-domain point mutations associated with Noonan Syndrome and leukemia.
J Proteomics. 2013; 84:132-47 [PubMed] Related Publications
UNLABELLED: SHP2/PTPN11 is a key regulator of cytokine, growth factor and integrin signaling. SHP2 influences cell survival, proliferation and differentiation by regulating major signaling pathways. Mutations in PTPN11 cause severe diseases like Noonan, LEOPARD syndrome or leukemia. Whereas several of these mutations result in altered enzymatic activity due to impaired auto-inhibition, not all disease patterns can be explained by this mechanism. In this study we analyzed altered binding properties of disease-related SHP2-mutants bearing point mutations within the SH2-domain (T42A, E139D, and R138Q). Mutants were chosen according to SPR assays, which revealed different binding properties of mutated SH2 towards phosphorylated receptor peptides. To analyze global changes in mutant binding properties we applied quantitative mass spectrometry (SILAC). Using an in vitro approach we identified overall more than 1000 protein candidates, which specifically bind to the SH2-domain of SHP2. We discovered that mutations in the SH2-domain selectively affected protein enrichment by altering the binding capacity of the SH2-domain. Mutation-dependent, enhanced or reduced exposure of SHP2 to its binding partners could have an impact on the dynamics of signaling networks. Thus, disease-associated mutants of SHP2 should not only be discussed in the context of deregulated auto-inhibition but also with respect to deregulated protein targeting of the SHP2 mutants.
BIOLOGICAL SIGNIFICANCE: Using quantitative mass spectrometry based proteomics we provided evidence that disease related mutations in SHP2 domains of SHP2 are able to influence SHP2 recruitment to its targets in mutation dependent manner. We discovered that mutations in the SH2-domain selectively affected protein enrichment ratios suggesting altered binding properties of the SH2-domain. We demonstrated that mutations within SHP2, which had been attributed to affect the enzymatic activity (i.e. affect the open/close status of SHP2), also differ in respect to binding properties. Our study indicates that SHP2 mutations need to be discussed not only in terms of deregulated auto-inhibition but also with respect to deregulated protein targeting properties of the SHP2 mutants. Discovery of the new binding partners for disease-related SHP2 mutants might provide a fruitful foundation for developing strategies targeting Noonan-associated leukemia.

Gaudineau A, Doray B, Schaefer E, et al.
Postnatal phenotype according to prenatal ultrasound features of Noonan syndrome: a retrospective study of 28 cases.
Prenat Diagn. 2013; 33(3):238-41 [PubMed] Related Publications
OBJECTIVE: Noonan syndrome is a frequent genetic disorder with autosomal dominant transmission. Classically, it combines postnatal growth restriction with dysmorphic and malformation syndromes that vary widely in expressivity. Lymphatic dysplasia induced during the embryonic stage might interfere with tissue migration. Our hypothesis is that the earlier the edema, the more severe postnatal phenotype.
METHOD: This retrospective study analyzed data from all 32 cases of Noonan syndrome diagnosed in the Medical Genetics Department of Hautepierre Hospital in Strasbourg, France, between 1995 and 2011. The postnatal evolution of Noonan syndrome was compared according to the presence of at least one prenatal ultrasound feature of lymphatic dysplasia.
RESULTS: The most frequent prenatal ultrasound features found were increased nuchal translucency, cystic hygroma and polyhydramnios; their global prevalence was 46.4%. The presence of these features was not significantly associated with the postnatal phenotype of Noonan syndrome.
CONCLUSION: The results of our study indicate that prenatal ultrasound features of lymphatic dysplasia do not predict an unfavorable postnatal prognosis for Noonan syndrome.

Ben-Shachar S, Constantini S, Hallevi H, et al.
Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.
Eur J Hum Genet. 2013; 21(5):535-9 [PubMed] Free Access to Full Article Related Publications
Neurofibromatosis type 1 (NF1) and its related disorders (NF1-Noonan syndrome (NFNS) and Watson syndrome (WS)) are caused by heterozygous mutations in the NF1 gene. Pulmonary stenosis (PS) occurs more commonly in NF1 and its related disorders than in the general population. This study investigated whether PS is associated with specific types of NF1 gene mutations in NF1, NFNS and WS. The frequency of different NF1 mutation types in a cohort of published and unpublished cases with NF1/NFNS/WS and PS was examined. Compared with NF1 in general, NFNS patients had higher rates of PS (9/35=26% vs 25/2322=1.1%, P value<0.001). Stratification according to mutation type showed that the increased PS rate appears to be driven by the NFNS group with non-truncating mutations. Eight of twelve (66.7%) NFNS cases with non-truncating mutations had PS compared with a 1.1% PS frequency in NF1 in general (P<0.001); there was no increase in the frequency of PS in NFNS patients with truncating mutations. Eight out of eleven (73%) individuals with NF1 and PS, were found to have non-truncating mutations, a much higher frequency than the 19% reported in NF1 cohorts (P<0.015). Only three cases of WS have been published with intragenic mutations, two of three had non-truncating mutations. Therefore, PS in NF1 and its related disorders is clearly associated with non-truncating mutations in the NF1 gene providing a new genotype-phenotype correlation. The data indicate a specific role of non-truncating mutations on the NF1 cardiac phenotype.

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