Skip to content

Advertisement

You're viewing the new version of our site. Please leave us feedback.

Learn more

BMC Medical Genetics

Open Access
Open Peer Review

This article has Open Peer Review reports available.

How does Open Peer Review work?

Mutation in NRAS in familial Noonan syndrome – case report and review of the literature

  • Sara Ekvall1,
  • Maria Wilbe1,
  • Jovanna Dahlgren2,
  • Eric Legius3,
  • Arie van Haeringen4,
  • Otto Westphal2,
  • Göran Annerén1 and
  • Marie-Louise Bondeson1Email author
BMC Medical Genetics201516:95

https://doi.org/10.1186/s12881-015-0239-1

Received: 17 April 2015

Accepted: 30 September 2015

Published: 14 October 2015

Abstract

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.

Keywords

NRAS Noonan syndromeMutationRAS-MAPK pathwayRASopathies

Background

Noonan syndrome (NS, OMIM 163950) is a relatively common developmental disorder belonging to the RASopathies, a group of clinically and genetically related syndromes [1, 2]. The molecular cause underlying RASopathies is dysregulation of the RAS-MAPK pathway and 15 different genes affecting this pathway have been associated to RASopathies. Of these 15 genes, eleven have been found to be involved in NS or NS-like conditions, where mutations in PTPN11 are the cause of ~50 % of the cases. The other genes are SOS1 [3, 4], CBL [57], BRAF [8], RAF1 [9, 10], SHOC2 [11], MAP2K1 [12], RIT1 [13], NRAS [14], KRAS [15, 16] and RRAS [17].

The main characteristics of NS are short stature, congenital heart defect, unusual pectus deformity and typical facial features, such as hypertelorism, ptosis, down-slanting palpebral fissures, low-set posteriorly rotated ears and a broad forehead. However, NS is a clinically variable disorder and additional associated features often present include neonatal failure to thrive, mild mental retardation, various skin manifestations, bleeding abnormalities and multiple skeletal defects [18, 19].

NRAS is a four-exon gene, encoding the widely expressed small GTPase NRAS, which act as a membrane-associated molecular switch in the RAS-MAPK pathway [14]. To date, only eight unrelated individuals with NS and three NS families have been identified with mutations in NRAS [14, 2023].

Here, we performed a comprehensive molecular analysis of 13 RASopathy-associated genes; NF1, PTPN11, SOS1, CBL, BRAF, RAF1, SHOC2, MAP2K2, MAP2K1, SPRED1, NRAS, HRAS and KRAS, in a family with NS, which revealed a previously reported mutation in NRAS, c.179G > A (p.G60E). We describe clinical features in this family and review the literature for genotype-phenotype correlations for NS patients with mutations in NRAS.

Case presentation

Clinical investigations and genetic analyses were performed according to the guidelines in the Declaration of Helsinki and approved by the ethical committee of Uppsala University and Gothenburg University, Sweden. Informed consent was obtained from all patients and specific permission was given for photographs.

Case 1

This is a 28-year-old woman, who got the clinical diagnosis of Noonan syndrome (NS) at the age of 4 years because of growth retardation, cardiomyopathy and facial features. She is the only child of non-related parents. The father (Case 2) has facial features of NS, but few additional clinical symptoms. She was born to a mother with diabetes during pregnancy with a birth weight of 4.7 kg (+3 SDS), a length of 52 cm (+1 SDS) and a head circumference of +2 SDS. She also had a large left ventricle, and a systolic murmur, but this disappeared at the age of six years. Postnatally, her growth decelerated and she had feeding difficulties. At 6.5 years of age, her height was 104 cm (−2 SDS) and her weight 18.5 kg (−2 SDS). She had low endogenous growth hormone (GH) secretion defined as “partial GH deficiency”, and started GH therapy within a formal clinical trial (NovoNordisk) from 6.5 years of age. She was treated with GH (dose of 66 μg/kg/day) and responded exceptionally well and treatment was discontinued after two years. However, at 10 years of age, she had her first pubertal signs and GH-treatment was started again using a standard dose of 33 μg/kg/day. At 12.3 years of age, she had menarche. The GH-treatment continued until final height (FH) was reached at the age of 14 years. Her FH is 164.5 cm (−0.45 SDS) and weight of 60 kg (+0.3 SDS). Her psychomotor development is normal, but she has slight problems of attention deficit. She attended regular school and works as an assistant nurse. At the age of 24 years, she has the following features of NS (Fig. 1a): a large skull (62 cm) with a broad forehead, hypertelorism, down slanted palpebral fissures, bilateral ptosis (especially of her left eye), short and broad neck with a low hairline, and low-set ears with broad helices. Her hair is normal. She has two large Café-au-lait spots on her back and >50 freckles (lentigines) all over her body, especially on her back (Fig. 1b) and arms (Fig. 1c).
Fig. 1

Photograph of the index patient affected by NS with a mutation in NRAS, p.G60E. a Facial features. b The back with multiple lentigines. c The left arm with multiple lentigines

Case 2

This is the 62-year-old father of Case 1. He was clinically diagnosed after Case 1 was diagnosed. He has facial features of NS, but few additional clinical symptoms. Sensorineural hearing impairment was present at birth. His growth pattern was normal, but he had a delayed puberty. His FH is 175.0 cm (−0.4 SDS) and weight 75 kg (±0 SDS). The intellectual development was normal. He followed normal school and university education and worked as a librarian until the age of 55 years, when he had to retire because of tinnitus. At the age of 62 years, he has the following features of NS (Fig. 2ac): slight macrocephaly (61 cm, +2 SDS), bilateral ptosis, hypertelorism and down-slanting palpebral fissures. He also has curly hair and lentigines on his back. He had a cardiac murmur in childhood that disappeared spontaneously.
Fig. 2

Photograph of the affected father with the same NRAS mutation, p.G60E. a Frontal facial features. b Additional facial features. c The back with multiple lentigines

Methods

Genomic DNA from the index patient and her father was extracted from peripheral blood leukocytes according to standard procedures.

Mutation analysis

The index patient was analyzed for variants in all coding exons and exon-intron boundaries of NF1 (NM_000267.3), PTPN11 (NM_002834), SOS1 (NM_005633), CBL (NM_005188), BRAF (NM_004333), RAF1 (NM_002880), SHOC2 (NM_007373), MAP2K2 (NM_030662), MAP2K1 (NM_002755), SPRED1 (NM_152594), NRAS (NM_002524), HRAS (NM_005343) and KRAS (NM_004985) using Agilent HaloPlex Target Enrichment (Agilent Technologies, Inc., Santa Clara, CA, USA), followed by next-generation sequencing on MiSeq, Illumina (Illumina, Inc., San Diego, CA, USA). Data analysis was performed by NextGENe software v2.3.1 (SoftGenetics, LLC., State College, PA, USA) and BENCHlab NGS (Cartagenia, Inc., Cambridge, MA, USA) [Ekvall et al. Manuscript in preparation].

Variants observed in NRAS exon 2 were verified by bi-directional Sanger sequencing in the index patient and her father. Primer sequences and PCR conditions are available upon request.

Results

DNA sequencing analysis of the index patient (Fig. 1) was performed on 13 RASopathy-associated genes using HaloPlex target enrichment (Agilent) and next-generation sequencing on MiSeq (Illumina). Coverage and read depth of the RASopathy genes in the index patient is shown in Table 1. Targeted bases in region of interest (ROI) with >30X read depth was 100 % for all genes, except NF1 (99.8 %) and SOS1 (99.9 %). No complementary Sanger sequencing was performed. A heterozygous missense mutation, c.179G > A; p.G60E, in exon 2 of NRAS was identified and verified using Sanger sequencing. This mutation was inherited from the father (Fig. 2), who also shows signs of NS. No additional variants of significance were identified in the index patient.
Table 1

Average read depth and coverage of RASopathy-associated genes in this study

Gene

Reference sequence

ROIa bases

Exons

Average read depth

Coverage >30X (%)

BRAF

NM_004333

3021

18

12 637

100. 0

CBL

NM_005188

3361

16

12 016

100.0

HRAS

NM_005343

812

6

14 291

100.0

KRAS

NM_004985

768

5

10 811

100.0

MAP2K1

NM_002755

1622

11

12 525

100.0

MAP2K2

NM_030662

1643

11

11 127

100.0

NF1

NM_000267

10737

58

12 728

99.8

NRAS

NM_002524

861

7

16 378

100.0

PTPN11

NM_002834

6521

16

16 262

100.0

RAF1

NM_002880

2587

16

15 985

100.0

SHOC2

NM_007373

2069

8

17 812

100.0

SOS1

NM_005633

4922

23

13 439

99.9

SPRED1

NM_152594

1615

7

10 509

100.0

aROI Region of interest

Conclusions

To date, only eight unrelated patients with NS and three NS families have been reported positive for NRAS mutations (p.G13D, p.I24N, p.P24L, p.T50I and p.G60E) [14, 2023]. In this study, we describe an additional family with NS, where the index patient and her father have c.179G > A (p.G60E). This mutation has been identified in both sporadic and familial NS patients of European origin [14, 23] and is the most common germline mutation in NRAS.

NS patients with NRAS mutations often show a relatively mild phenotype of typical Noonan facial features. A comparison of previously reported NRAS-associated NS cases shows that all of the patients present with typical Noonan facial features (14/14) and 11/13 have macrocephaly or relative macrocephaly, but only half of them display congenital heart defects (7/14). All previously reported patients also show short stature. However, in the family reported here the father’s height was normal, while the daughter had short stature successfully treated with GH. The majority has pterygium or webbing of the neck (10/12). Thorax deformity (pectus excavatum) occurs in 5/14 patients, while easy bruising is less common (3/14). Half of the males show cryptorchidism (6/10) and ophthalmological problems appear in 4/14 patients. Motor delay is common (9/14 patients) and as previously reported, intellectual development is often mildly delayed (6 patients normal and 8 mildly delayed). Keratosis pilaris/hyperkeratosis is less common (4/12 patients) and hair abnormalities occur in about half of the patients. Of note, lentigines are observed in six patients, but leukemia/cancer are rarely seen (1 patient with JMML) (Table 2) [14, 2023]. Somatic mutations affecting genes in the RAS-MAPK pathway are associated with cancer, and NS and related disorders are known to cause a predisposition to cancer [24]. Somatic mutations in NRAS are involved in the development of hematological malignancies and in a variety of solid tumors (COSMIC database; http://cancer.sanger.ac.uk/). However, germline NRAS mutations differ from most common somatic NRAS mutations associated with malignancies and are less activating in dysregulating intracellular signaling [18].
Table 2

Clinical features of patients with Noonan syndrome caused by NRAS mutations

#

1

2

3

4

5

6

7

8

9

9 M

10

11

12

12 F

Patient

De Filippi et al. [20]

Runtuwene et al. [21]

Denayer et al. [22]

Denayer et al. [22]

Denayer et al. [22]

Cirstea et al. [14]

Cirstea et al. [14]

Cirstea et al. [14]

Cirstea et al. [14]

Cirstea et al. [14]

Kraoua et al. [23]

Kraoua et al. [23]

Present study

Present study

NRAS mutation

p.G13D

p.I24N

p.I24N

p.P24L

p.T50I

p.T50I

p.T50I

p.G60E

p.G60E

p.G60E

p.G60E

p.G60E

p.G60E

p.G60E

Origin of mutation

de novo

de novo

de novo

Inherited

ND

de novo

de novo

de novo

Inherited

ND

ND (probably inherited)

de novo

Inherited

ND (probably inherited)

Paternal age at conception

ND

26 years

ND

ND

ND

50 years

34 years

31 years

47 years

44 years

45 years

47 years

34 years

ND

Age at last examination

3 years

30 years

13 years

19 years

2.5 years

14 years

7 years

3.3 years

20 years

50 years

24 years

3 months

28 years

62 years

Gender

Male

Male

Male

Male

Male

Male

Male

Female

Male

Female

Male

Female

Female

Male

Prenatal findings

ND

Polyhydramnios

ND

ND

ND

Nuchal edema, Polyhydramnios

Polyhydramnios

Single umbilical artery

-

-

Polyhydramnios

Pyelectasis

-

-

Congenital heart defect

-

-

-

ND

Coarctation aortae, Patent foramen ovale

HCM

PS

Mild HCM, Mitral valve dysplasia, PS

-

-

-

PS

ASD, HCM

Cardiac murmur

Rythm disturbance

ND

-

ND

ND

-

SVES

-

-

-

-

-

-

-

-

Typical facial features

+

+

+

+

+

+

+

+

+

+

+

+

+

+

Stature

5–10th centile

Mild short

<3rd centile

10th–25th centile

10th–25th centile

10th centilea

<3rd centile

<3rd centile

>10th centile

10th centile

3rd centile

3rd–10th centile

50th centilea

50th centile

Macrocephaly

Relative

>90th centile

>97th centile

ND

25th–50th centile

+

Relative

-

+

+

Relative

Relative

+

Relative

Pterygium colli/Webbed neck

-

+

ND

ND

+

+

-

+

+

+

+

+

+

+

Thorax deformity

-

Pectus excavatum

Pectus excavatum

ND

Pectus excavatum

+

-

Pectus excavatum

+

+

Mildly depressed thorax

Pectus excavatum

-

-

Easy bruising

-

-

ND

+

ND

-

-

-

-

-

+

ND

+

-

Cryptorchidism

-

+

+

ND

+

+

+

NA

+

NA

-

NA

NA

-

Ophthalmological problems

ND

-

Strabismus, Bilateral keratoconus of the cornea

ND

ND

Myopia

-

-

-

Myopia

-

-

Astigmatis, Myopia, Strabismus

-

Motor delay/Muscular hypotonia

-

Motor delay

Mild

ND

ND

Mild

+

+

+

+

Mild

+

-

-

Mental development

Normal

Mild learning difficulties

Normal

Learning difficulties

Normal

Normal

Borderline

Speech delay

Normal-borderline

Normal

Speech delay, dyscalculy

NA

ADHD, normal IQ

Normal

Keratosis pilaris/Hyperkeratosis

ND

-

ND

ND

ND

Severe

-

+

+

+

ND

-

-

-

Hair abnormalities

-

-

ND

ND

ND

Curly hair

Curly hair

Sparse thin hair

Curly hair

-

-

Curly hair

-

Curly hair

Lentigines/Café-au-lait spots

+

Some lentigines

-

-

-

-

-

-

-

-

+

+

+

+

Leukemia/Cancer

JMML

-

-

-

-

-

-

-

-

-

-

-

-

-

Other

-

Oligospermia

-

Inadequate visio-spatial orientation skills, Inguinal hernia, Delayed pubertal development

-

Pes equinovarus

-

Palpebral ptosis

Ichtyosiform eczema, Acanthosis nigricans, Scoliosis

Mother of patient 9

Palpebral ptosis, Inguinal hernia, Scoliosis

Palpebral ptosis, Unilateral pyelectasis

-

Sensory-neural hearing deficit, Father of patient 12

ASD atrial septal defect, HCM hypertrophic cardiomyopathy, JMML juvenile myelomonocytic leukemia, NA not applicable, ND not determined, PS pulmonic stenosis, SVES supraventricular extrasystole

aReceived growth hormone treatment from the age of 8 years, when partial growth hormone deficiency had been noted

In summary, we report an NS family with a p.G60E in NRAS. Neither of affected individuals presented with JMML. Thus, the proportion of JMML observed in NRAS patients (1/12) is comparable with the observed proportion of JMML in NS in general [25].

Interestingly, half of the patients (including affected individuals in our family) presented with lentigines and/or Café-au-lait spots, which is high compared to the prevalence of 3 % for lentigines and 10 % for Café-au-lait spots in the general NS population [26]. Multiple nevi, lentigines and/or Café-au-lait spots are also detectable in one-third of NS individuals with a RAF1 mutation and previous studies have demonstrated a higher prevalence of these features in BRAF-positive NS individuals as well. This suggests that NS individuals with a mutation in NRAS, RAF1 or BRAF have a predisposition to hyperpigmented cutaneous lesions [8, 27]. Of note, the father in our family presented with congenital sensorineural hearing impairment, which together with lentigines are two common features in Noonan syndrome with multiple lentigines (NS-ML, previously LEOPARD syndrome). This demonstrates the wide spectrum of phenotypes within each syndrome as well as the clinical overlap between RASopathies, which makes diagnosis of NS and related disorders challenging.

However, by using the advent of next-generation sequencing technology, which allow for screening of a large number of genes simultaneously, an early and accurate genetic diagnosis of patients with RASopathies will be facilitated.

Consent

We have obtained written informed consent from the patients for publication of this case report and accompanying images. A copy of the written consent is available from the Editor of this journal.

Abbreviations

NS: 

Noonan syndrome

MAPK: 

Mitogen-activated protein kinase

JMML: 

Juvenile myelomonocytic leukemia

GH: 

Growth hormone

ROI: 

Region of interest

COSMIC: 

Catalogue of somatic mutations in cancer

ASD: 

Atrial septal defect

HCM: 

Hypertrophic cardiomyopathy

NA: 

Not applicable

ND: 

Not determined

PS: 

Pulmonic stenosis

SVES: 

Supraventricular extrasystole

Declarations

Acknowledgements

This study was supported by grants from the Swedish Research Council, the Borgström foundation, the Sävstaholm foundation and foundations at the Medical Faculty of Uppsala University, Sweden. The authors wish to thank the family for participating in this study.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University
(2)
Department of Paediatrics, the Sahlgrenska Academy, Gothenburg University
(3)
Department of Human Genetics, KU Leuven
(4)
Department of Clinical Genetics, Leiden University Medical Center

References

  1. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381(9863):333–42.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Tartaglia M, Gelb BD. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms. Ann N Y Acad Sci. 2010;1214:99–121.View ArticlePubMedPubMed CentralGoogle Scholar
  3. Roberts AE, Araki T, Swanson KD, Montgomery KT, Schiripo TA, Joshi VA, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nat Genet. 2007;39(1):70–4.View ArticlePubMedGoogle Scholar
  4. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007;39(1):75–9.View ArticlePubMedGoogle Scholar
  5. Martinelli S, Checquolo S, Consoli F, Stellacci E, Rossi C, Silvano M, et al. Loss of CBL E3-ligase activity in B-lineage childhood acute lymphoblastic leukaemia. Br J Haematol. 2012;159(1):115–9.View ArticlePubMedGoogle Scholar
  6. Niemeyer CM, Kang MW, Shin DH, Furlan I, Erlacher M, Bunin NJ, et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010;42(9):794–800.View ArticlePubMedPubMed CentralGoogle Scholar
  7. Perez B, Mechinaud F, Galambrun C, Ben Romdhane N, Isidor B, Philip N, et al. Germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia. J Med Genet. 2010;47(10):686–91.View ArticlePubMedGoogle Scholar
  8. Sarkozy A, Carta C, Moretti S, Zampino G, Digilio MC, Pantaleoni F, et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat. 2009;30(4):695–702.View ArticlePubMedPubMed CentralGoogle Scholar
  9. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39(8):1007–12.View ArticlePubMedGoogle Scholar
  10. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, et al. Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet. 2007;39(8):1013–7.View ArticlePubMedGoogle Scholar
  11. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022–6.View ArticlePubMedPubMed CentralGoogle Scholar
  12. Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007;44(12):763–71.View ArticlePubMedPubMed CentralGoogle Scholar
  13. Aoki Y, Niihori T, Banjo T, Okamoto N, Mizuno S, Kurosawa K, et al. Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome. Am J Hum Genet. 2013;93(1):173–80.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Cirstea IC, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D, et al. A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2010;42(1):27–9.View ArticlePubMedGoogle Scholar
  15. Carta C, Pantaleoni F, Bocchinfuso G, Stella L, Vasta I, Sarkozy A, et al. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. 2006;79(1):129–35.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Schubbert S, Zenker M, Rowe SL, Boll S, Klein C, Bollag G, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. 2006;38(3):331–6.View ArticlePubMedGoogle Scholar
  17. Flex E, Jaiswal M, Pantaleoni F, Martinelli S, Strullu M, Fansa EK, 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.View ArticlePubMedPubMed CentralGoogle Scholar
  18. Allanson JE. Noonan syndrome. J Med Genet. 1987;24(1):9–13.View ArticlePubMedPubMed CentralGoogle Scholar
  19. van der Burgt I. Noonan syndrome. Orphanet J Rare Dis. 2007;2:4.View ArticlePubMedPubMed CentralGoogle Scholar
  20. De Filippi P, Zecca M, Lisini D, Rosti V, Cagioni C, Carlo-Stella C, et al. Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia. Br J Haematol. 2009;147(5):706–9.View ArticlePubMedGoogle Scholar
  21. Runtuwene V, van Eekelen M, Overvoorde J, Rehmann H, Yntema HG, Nillesen WM, et al. Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. Dis Model Mech. 2011;4(3):393–9.View ArticlePubMedPubMed CentralGoogle Scholar
  22. Denayer E, Peeters H, Sevenants L, Derbent M, Fryns JP, Legius E. NRAS Mutations in Noonan Syndrome. Mol Syndromol. 2012;3(1):34–8.PubMedPubMed CentralGoogle Scholar
  23. Kraoua L, Journel H, Bonnet P, Amiel J, Pouvreau N, Baumann C, et al. Constitutional NRAS mutations are rare among patients with Noonan syndrome or juvenile myelomonocytic leukemia. Am J Med Genet A. 2012;158A(10):2407–11.View ArticlePubMedGoogle Scholar
  24. Kratz CP, Franke L, Peters H, Kohlschmidt N, Kazmierczak B, Finckh U, et al. Cancer spectrum and frequency among children with Noonan, Costello, and cardio-facio-cutaneous syndromes. Br J Cancer. 2015;112(8):1392–7.View ArticlePubMedPubMed CentralGoogle Scholar
  25. Strullu M, Caye A, Lachenaud J, Cassinat B, Gazal S, Fenneteau O, et al. Juvenile myelomonocytic leukaemia and Noonan syndrome. J Med Genet. 2014;51(10):689–97.View ArticlePubMedGoogle Scholar
  26. Noonan Syndrome.[http://www.ncbi.nlm.nih.gov/books/NBK1124/]
  27. Tartaglia M, Zampino G, Gelb BD. Noonan syndrome: clinical aspects and molecular pathogenesis. Mol Syndromol. 2010;1(1):2–26.View ArticlePubMedPubMed CentralGoogle Scholar

Copyright

© Ekvall et al. 2015

Advertisement