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The Clinical Spectrum of RASopathies

Divya Agarwal, Ratna D Puri, Achint Kaur, Sunita Bijarnia-Mahay and IC Verma
Center of Medical Genetics, Sir Ganga Ram Hospital, New Delhi
Email: dr.divya2512@gmail.com

1 Introduction

The RASopathies are a specific group of genetic syndromes that occur as a result of germline mutations in genes encoding proteins of the Ras–mitogen-activated protein kinase (RAS–MAPK) pathway (Fig 1). These developmental disorders include Neurofibromatosis type 1 (NF1), the first RASopathy identified, followed by Noonan syndrome (NS), and a host of others including Noonan syndrome with multiple lentigines (NSML), capillary malformation–arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC) and Legius syndrome. The Ras-MAPK pathway is essential for signal transduction from the cell surface to the nucleus and plays a pivotal role in regulation of cellular proliferation, differentiation and cellular growth. The RAS multigene family includes KRAS, HRAS and NRAS and code for Ras proteins that are guanosine nucleotide bound and cycle between the active GTP-bound form and the inactive GDP-bound form. Activation of RAS occurs as an outcome of binding of the growth factor to the receptor tyrosine kinase (RTK) and SOS1 recruitment, that in turn increases the active GTP-bound Ras form. This further initiates activation of Raf (ARAF, BRAF, CRAF), the first MAPK pathway kinase, which in turn activates MEK1 / MEK2, which then regulate the downstream effector substrates ERK1and ERK2. These further activate downstream nuclear and cytosolic molecules that control cellular proliferation and differentiation (Fig 1) (Tidyman and Rauen, 2009). Understanding the pathophysiology is important to identify possible therapeutic targets for RASopathies, aimed at reduction of activity of RAS signaling (Korf B, et al., 2015; Bezniakow N, et al., 2014).


 Figure 1: Ras-MAPK signal transduction pathway and molecular basis of RASopathies. NF-1: Neurofibromatosis type 1; NS: Noonan syndrome; CFC: Cardiofaciocutaneous syndrome; CS: Costello syndrome; LS: Legius syndrome; NSML: Noonan syndrome with multiple lentigines; CM-AVM: Capillary malformation-arteriovenous malformation.

In the group of malformation syndromes that occur due to the Ras / MAPK pathway dysregulation, germline mutation in any of the genes exhibits numerous overlapping phenotypic features of facial dysmorphism, short stature, congenital heart defects (CHD), skeletal abnormalities, cutaneous abnormalities and variable developmental delay.

These are one of the largest group of malformation syndromes with an estimated incidence of about 1 in 1000 persons. Activating mutations in PTPN11 are present in 50% patients with Noonan syndrome, other causative genes being SOS1, RAF1, KRAS, NRAS, SHOC2, CBL and MAP2K1 (MEK1) which are implicated in a subset of patients. Genes associated with the other disorders of this pathway are illustrated in Figure 1. Recently, novel gene variants, including RIT1, RRAS, RASA2, A2ML1, SOS2 and LZTR1, have in addition been shown to be associated with RASopathies, further expanding the disease spectrum (Aoki Y et al., 2016). Table 1 lists the various genes responsible for causing Noonan and Noonan-like syndromes.

 Table  1: Genes responsible for causing RASopathies.

RAS/MAPK pathway gene
Proportion of disease attributed to this gene

Neurofibromatosis 1



Noonan Syndrome (NS)










4 individuals to date








Noonan syndrome with multiple lentigines






2 individuals


1 individual

Capillary malformation-arteriovenous malformation



Costello syndrome



Cardio-facio-cutaneous syndrome








Legius syndrome



Novel genes in NS and NS like syndromes (No. of families reported)

RIT1, RRAS, RASA2, A2ML1, SOS2, LZTR1 (Bezniakow N, et al., 2014; Korf et al., 2015; Aoki et al., 2016; Allanson & Roberts, 2011)

We discuss here a few of the interesting cases that presented to the genetic clinic at our hospital from 2012 through December 2015, with characteristic features of Noonan and other RASopathies. Neurofibromatosis type 1 is not included in this series except one case of NF1 with developmental delay and craniofacial dysmorphism reminiscent of NS. A total of 20 patients including 13 patients with a provisional diagnosis of Noonan syndrome (NS), 5 patients with a diagnosis of Cardiofaciocutaneous syndrome (CFC), 1 patient with suspected NF - Noonan syndrome and 1 patient of Costello syndrome were seen during this time. The age of presentation varied from 3 months to 22 years and one fetus was evaluated after termination of the pregnancy at 18 weeks gestation. The clinical data of the patients is presented in the Table 2.

2 Cranio-facial dysmorphism

The most consistently found feature in all patients was the characteristic facial dysmorphism - low set and posteriorly rotated ears, broad nasal bridge, hypertelorism and downslanting palpebral fissures seen in 17/20 (85% of patients). Additionally ptosis was noted in 12/20 (60% of patients) (Fig 2A). In patients with clinical suspicion of cardiofaciocutaneous syndrome (5/20 patients), the face was broader and coarse looking with sparse, thick, curly wooly hair (Fig 2B). In our one patient of Costello syndrome (Table 2-IV) from Nigeria, the facies were much more coarse with thick, fleshy earlobes, full nasal tip and thick lips (Fig 2C; the mother’s photo given for comparison). The facial features associated with NS and related disorders vary considerably with age, being most striking in the neonatal period and childhood. Since the presentation can be mild and the typical facies recede with age, the diagnosis may be overlooked. Hence, the facial dysmorphism should be carefully noted at the initial visit as “gestalt” assessment is the commonest diagnostic tool for disorders of the RAS-MAPK pathway.


 Figure 2: Facial features of patients with suspected Noonan syndrome (A), Cardio-facio-cutaneous syndrome (B) and Costello syndrome (C).

 Table  2: Clinical characteristics and mutations of patients with suspected Noonan Syndrome (I.1-I.13), Cardiofaciocutaneous syndrome (II.1-II.5), Neurofibromatosis Noonan syndrome – NFNS (III), Costello syndrome-(IV).

Patient ID
Age at presentation /Sex
Development /Intellect
Heart disease
Facial features
Others/ Mutation


18 weeks fetus / M

Bilateral hypoplastic kidneys with oligohydramnios. Echocardiography- Pulmonary stenosis.


Crown rump length: 18 cms (18-19 weeks)

Pulmonary stenosis

Telecanthus, broad nose, low set ears, downslanting palpebral fissures

Normal radiographs



3 months / M

NT-5.6 mm, Femur - 5th centile for gestation, Antenatal Karyotype- 46,–, Normal


59 cms (50th centile)

not present

Sparse eyebrows, downslanting eyes, triangular chin, low set ears, high arched palate, bulbous tip of nose

Right CTEV, limitation of elbow joint extension, right clinodactyly.


5.5 months / M

Antenatal data not available.


55.6 cms (- 4 SD)

Hypertrophic cardiomyopathy

Downslanting eyes, Bulbous nasal tip

Short neck, shield like chest, wide spaced nipples



5.5 months / M

Antenatal period- uneventful

Global development delay

56 cms (-4SD)

Atrioventricular canal defects

No dysmorphic features


Juvenile myelomonocytic leukemia, feeding difficulty & vomiting, retrocollis failure to thrive, loose skin, scant hair. Heterozygous mutation (c.218C>T, p.Thr73Ile) in PTPN11 gene


10 month / M

Antenatal data not available


63 cms (-3 SD)

ASD with severe valvular pulmonary stenosis

Downslanting eyes


Feeding difficulty & vomiting, bilateral undescended testes


1 year / M

Antenatal data not available


70 cms (-2 SD)

Severe valvular pulmonary stenosis with RVH

Facial asymmetry, left ptosis, hypertelorism, epicanthic folds

Bilateral 2nd-3rd toe syndactyly, left Simian crease



4 years / M

Antenatal data not available

Mild development delay

90 cms (-2 to -3 SD)

Atrial septal defect

Downslanting eyes, hypertelorism


Undescended testes, hypospadias


4 years / M

Antenatal data not available


91 cms (-3 to -2 SD) at diagnosis

Atrialseptal defect

Ptosis, broad nasal bridge


On Growth hormone therapy


4.5 years / M

Antenatal data not available


88 cms (-5 to -4 SD) at diagnosis

Supravalvular tethering of pulmonary valve

Mild ptosis, depressed nasal bridge

Winging of scapula, pectus excavatum, short neck, limitation of elbow extension

On Growth hormone therapy


7 years / M

Antenatal data not available

Development delay present

100.5 cms (-4 SD)

Soft systolic murmur, recurrent respiratory infections. Echo - Not done.

Downslant palpebral fissures, low set ears, small philtrum, teeth pigmentation

Short neck, small hands and feet

CT head- Hydrocephalus Heterozygous mutation (c.2536G>A, p.Glu346Lys) in exon 16 of SOS1 gene


10 years 8 month / F

Antenatal data not available

Mild ID

111 cms (-5 SD)

Echocadiography - Normal


Short neck, pectus carinatum


14 years / F

Antenatal data not available

Mild ID

135 cms (-3 SD)

Pulmonic stenosis

Epicanthal folds, hypertelorism, low nasal bridge, downward eye slant, low set ears




22 years / M

Antenatal data not available

Mild ID

158 cms

CHD- Unspecified

Broad nasal bridge, maxillary hypoplasia, small curved eyelashes, preauricular sinus

Bilateral pedal edema, broad laterally deviated toes



1 year / F

Unilateral hydronephrosis

Severe development delay

68 cms (-3 to -2 SD)

Pulmonary stenosis

Depressed nasal root, wide base of nose, bulbous tip


Feeding difficulty with GERD


3 years / F


Mild global development delay

87 cms (3- 50th centile)

Left ventricle hypertrophy, left ventricle dysfunction, mild mitral regurgitation

Coarse facies, downslant palpebral fissures, low set ears, broad forehead, hypertelorism, strabismus

Short broad thumbs, fingers and toes, widely spaced nipples

Generalised dry skin, keratosis pilaris,sparse eyebrows, curly wooly hair


5 years / M

Antenatal data not available

Moderate ID

95 cms (-3 to -4SD)

Atrial septal defect

Coarse, broad face, downslanting palpebral fissures, bulbous tip of nose.


Curly wooly hair


8 years / M

Antenatal data not available

Moderate ID

115 cms (-2 to -3SD)

Hypertrophic cardiomyopathy

Coarse, broad face. downslanting palpebral fissures, bulbous tip of nose. ptosis


Curly hair


18 months / M


Mild development delay

73 cms (-3 SD)

Atrial septal defect

Coarse, broad face. downslanting palpebral fissures, bulbous tip of nose.


Curly, scant hair


15 months / M

Antenatal data not available

Mild development delay

71 cms (-3 SD)


Downslanting palpebral fissures, bulbous tip of nose


Multiple café au lait spots, plexiform neurofibroma Heterozygous mutation (c.2033dupC) in exon 18 of NF1 gene


6 year / F

Antenatal data not available

Delayed psychomotor development

107 cms (5th to 25th centile)

Hypertrophic cardiomyopathy

Coarse facies, broad forehead, depressed nasal bridge, epicanthic folds, hypertelorism, thick, fleshy earlobes, full nasal tip, thick lips

Sparse, fine scalp hair, skin - small papilloma at the root of the nasal tip was noticed, hyperkeratosis of palms & soles

NT: nuchal translucency; CTEV: congenital Talipes equinovarus, ID: intellectual disability; M: male; F: female; RVH: right ventricular hypertrophy; GER: gastro-esophageal reflux.

3 Cardiac manifestations

Heart disease was present in 17 out of 20 patients (85%) similar to the estimated frequency between 50 - 80% (Allanson & Roberts, 2011). NS and related disorders are one of the most common syndromic cause of heart defects. Several cardiovascular phenotypes are found, with pulmonary valvular stenosis being the most common in our cohort followed by hypertrophic cardiomyopathy and atrial septal defects.

4 Growth

Neonates with NS usually have normal birth weight and body length. Infants, however have feeding difficulties that result in failure to thrive, most evident in the first year of life. Severe feeding difficulty and gastroesophageal reflux disease were present in three of our patients (Table 2- I.4, I.5, II.1), requiring prolonged gastrostomy in one of them.

In childhood, short stature is almost a universal finding and height usually follows the third centile with an attenuated pubertal spurt. A study reported that 30% of individuals with Noonan syndrome have a height in the normal adult range while 40 – 50% individuals have an adult height below the third centile (Noonan et al., 2003). This may be due to growth hormone deficiency because of neurosecretory dysfunction or growth hormone resistance. The US Food and Drug Administration in 2007 approved Growth Hormone (GH) replacement therapy with recombinant human growth hormone for Noonan Syndrome. Several long and short term studies on the use of GH in different parts of the world reveal significant improvement in the height velocity in children with NS (Tamburrino et al., 2015; Romano et al., 2009; Noordam et al., 2008; Osio et al., 2005; Ogawa et al., 2004).

In our study cohort, sparing an adult and a fetus, short stature was recorded in all the patients. Two patients have been receiving growth hormone therapy for a few years. One of the boys (Table 2- I.9) had height at -5 to - 4 SD at 4.5 years of age, delayed bone age, low IGF-1 levels and inadequate response to clonidine in growth hormone stimulation test. On receiving an average 0.15 units/ kg /day of GH subcutaneously, he showed significant increase in height velocity initially and gained 7.5 cm in the first year of therapy. At 14 years of age, his height is at -2SD from the mean (comparable to the mid parental height centile). For the second boy (Table 2- I.8) who received growth hormone treatment, GH was initiated at 0.15 units/kg/day from 4 years of age. The height increased from -3 SD to -2 SD within 3 years of initiation of therapy. However, it has not increased beyond -2 SD from the mean demonstrating a short-term increase in growth. There were no complications of hypertrophic cardiomyopathy or hematologic disturbances in these patients.

Occasionally NS is referred to as ‘Pseudo-Turner or Male Turner syndrome’, due to similar findings of short stature, webbed neck and lymphedema. Interestingly, we had one girl (Table 2- I.10) who was evaluated for short stature. The karyotype revealed 45,X [3] / 46, XX [47] confirming the diagnosis of mosaic Turner syndrome. However, she also had some characteristic NS-like craniofacial dysmorphism and systemic malformations - epicanthic folds, hypertelorism, low nasal bridge, downward eye slant, low set ears, pulmonary stenosis and lentigines. Molecular panel testing for Noonan-related genes identified a heterozygous mutation (c.2536G>A) in the SOS1 gene that has been implicated in Noonan syndrome.

5 Psychomotor development

In most affected individuals of NS, intelligence is within the normal range, with the intelligence quotient ranging from 70-120. Mild to severe learning disability is reported in 25% and 10% of the patients respectively. Furthermore, in literature it has been noted that the verbal performance is significantly lower than the non-verbal performance. In contrast, neurologic abnormalities have been reported to be universally present in CFC and range from mild to severe (Yoon et al., 2007). In our cohort of NS patients, development / intellect was appropriate for age in 54% (7/13) of patients. The children with a clinical diagnosis of CFC syndrome and Costello syndrome in the cohort had global development delay that was of mild to moderate severity.

6 Dermatological manifestations

Among the RASopathies, the dermatologic findings are the most common in cardiofaciocutaneous syndrome (CFC). These include xerosis, hyperkeratosis, ichthyosis, keratosis pilaris, ulerythema ophryogenes, eczema, pigmented moles, hemangiomas, and palmoplantar hyperkeratosis. The hair is typically sparse, curly, fine or thick, wooly or brittle; eyelashes and eyebrows may be absent or sparse. Nails may be dystrophic or fast growing. Apart from these similar features, Costello syndrome is characterised by papillomas of face and perianal region, as also found in our patient IV (Fig 3).


 Figure 3: Patient IV- Costello syndrome. (A) Skin papilloma (B) Deep skin creases (C) Hyperkeratosis.

Patients with NF1 have café au lait spots, axillary freckling and neurofibromas in skin. NS may also have skin manifestations, particularly follicular keratosis over extensor surfaces, lentigines and café-au-lait spots. One child in the current cohort (Table 2-III) presented with clinical features characteristic of both neurofibromatosis type 1 and Noonan syndrome (NFNS syndrome- OMIM 601321). The NF1 features at presentation were > 6 café-au-lait spots. Follow up MRI identified cervical plexiform neurofibroma (Fig 4A, 4B). In addition the child had short stature, hypertelorism, ptosis, nystagmus, low-set ears, webbed neck and pectus deformity suggestive of NS. Mutation analysis revealed a heterozygous truncation mutation in NF1:c.2033dupC, thereby confirming the diagnosis of NFNS. The parents were normal on clinical examination. Recently, a similar report of a family with multiple café au lait spots and NS-like facial features in a child (fulfilling criteria of NF1) and mother (not fulfilling criteria for NF1) revealed mutation in MAP2K2 gene (Takenouchi et al., 2014). This gene has been originally implicated in CFC syndrome which further illustrates the phenotypic and genetic overlap in RASopathies.


 Figure 4: Patient III (A) Café au lait spots (B) Plexiform Neurofibroma.

7 Leukemias and other malignancies

Individuals with Noonan syndrome have upto three fold increased risk of malignancies which include juvenile myelomonocytic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia and solid tumours such as rhabdomyosarcoma and neuroblastoma (Jongmans et al., 2011; Strullu et al., 2014).

In particular, individuals with germline mutations in the PTPN11 gene have a predisposition to Juvenile myelomonocytic leukemia (JMML) (Strullu et al., 2014). In our cohort, patient I.4 was diagnosed with JMML at 3 months of age. He also had atrioventricular canal defect, feeding difficulties and severe failure to thrive. In view of these, he was clinically suspected and found to be carrying a heterozygous mutation in the PTPN11 gene (c.218C>T, p.T73I), confirming the diagnosis of Noonan syndrome. This mutation has been previously identified in multiple Noonan patients with JMML, with a milder clinical course (Aoki et al., 2008).

8 Prenatal Diagnosis

For prenatal diagnosis, the ultrasonographic markers for NS are non specific. In the absence of family history NS is not routinely suspected and prenatal testing is not typically offered. In our cohort, the antenatal data of five patients was available and showed abnormalities. One patient (Table 2-I.2) had increased nuchal fold thickness (NFT) of 5.6 mm with femur length at 5th centile and polyhydramnios in the 2nd trimester scan. Fetal chromosomes were tested and were normal. The neonate came to medical attention at 3 months of age for dysmorphism and joint movement restriction.

One fetus (Table 2-I.1) which was terminated in view of increased NFT (5.68 mm), bilateral hypoplastic kidneys and severe pulmonary stenosis on antenatal ultrasound at 18 weeks gestation was clinically diagnosed with Noonan syndrome in view of the facial phenotype.

The other three patients (Table 2-II.1, II.2, II.5) who had antenatal polyhydramnios and unilateral hydronephrosis came to medical attention after birth for developmental delay, facial dysmorphism and congenital heart disease.

The prenatal features described for NS are increased nuchal translucency (NT), distended jugular lymphatic sacs (JLS), cystic hygroma, hydrops fetalis, pleural effusion, polyhydramnios, congenital heart disease and renal abnormalities (Myers et al., 2014).

Out of these, increased NT has the strongest association with Noonan syndrome. However, there is considerable debate as to when to offer prenatal molecular testing for Noonan syndrome, either following a first trimester increased NT or if there are associated anomalies in the 2nd trimester scan with normal fetal chromosomes.

In recent studies in fetuses with an increased NT and a normal karyotype, mutations have been reported in 9–18% of cases. Lee et al. (2009) identified PTPN11 mutations in 2% of fetuses with increased NT and 16% of fetuses with increased NT and cystic hygroma. In another study, in fetuses with increased NT and normal karyotype, PTPN11 and KRAS mutations were found in 15.8%. This group strongly advocated genetic counseling and testing for Noonan syndrome in case of increased NT and normal karyotype, even in the absence of additional associated abnormalities (Houweling et al., 2010). On the other hand, Croonen et al. (2013), based on their mutation detection rate of 17.3% in fetuses with ultrasound findings of increased NT, distended jugular lymphatic sacs (JLS), hydrothorax, renal anomalies, polyhydramnios, cystic hygroma, cardiac anomalies, hydrops fetalis and ascites, recommended prenatal testing of PTPN11, KRAS and RAF1 in pregnancies with an increased NT and at least one of the additional ultrasonologic features.

In conclusion, Noonan syndrome and the other RASopathies have multisystem morbidities. The clinical features are overlapping and there is extensive genetic heterogeneity. In case of antenatal or postnatal clinical suspicion, with availability of next generation panel testing, the genes in the Ras/MAPK pathway implicated with the phenotypes of RASopathies can be tested for confirmation of diagnosis. Furthermore, in view of multisystemic involvement, multidisciplinary management and follow up of diagnosed patients is essential.


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