Noonan syndrome

What is Noonan syndrome?

A genetic disorder that presents with unusual facial characteristics and short stature. Health conditions associated with this disorder include eczema, developmental delay, short stature, webbed neck, pulmonic stenosis, and unique facial features. It is an inherited genetic condition, and just one copy of the mutated gene in each cell is enough to cause the disorder.

Syndrome Synonyms
Female Pseudo-turner Syndrome, Male Turner Syndrome, Noonan Syndrome, Turner Phenotype With Normal Karyotype

What gene changes cause Noonan syndrome?

Noonan syndrome is part of a group of related conditions known as RASopathies. Changes in one of several autosomal-dominant genes cause the syndrome. Around half of all cases are caused by mutations in the PTPN11 gene, with a further 10-15% of cases caused by SOS1 gene mutations. Mutations in the RAF1 and RIT1 genes are accounting for around 5% of cases. And a further 15-20% of cases present with cause unknown. The PTPN11, SOS1, RAF1, and RIT1 genes are responsible for providing the instructions for making proteins needed for cell division and growth. Mutations in the genes associated with Noonan syndrome cause this protein to be active longer than normal rather than switching on and off in response to cell signals. This then disrupts cell growth regulation and leads to characteristic clinical features of Noonan syndrome.

In the case of autosomal dominant inheritance just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.


Genes, locations, and inheritance modes
RRAS, 19q13.33 - Autosomal Dominant

OMIM Number - 163950 (please check the OMIM page for updated information)

What are the main symptoms of Noonan syndrome?

The main symptoms of Noonan syndrome include characteristic facial features such as a deep groove between the nose and mouth, widely spaced eyes that are often pale blue or blue-green, and low-set ears rotated backward. A high arch in the roof of the mouth, a small lower jaw, and excess neck skin or webbing are also all characteristic of the syndrome. Children with Noonan syndrome are often both a normal length and weight at birth, but their growth slows over time. Individuals with the syndrome may also have a sunken or protruding chest.

Congenital heart disease can also be a symptom of Noonan syndrome, specifically a narrowing of the valve that controls blood flow from the heart to the lungs. Individuals may also present twitch hypertrophic cardiomyopathy, which enlarges and weakens the heart muscle.

Eczema and bleeding disorders are also a dominant symptom of Noonan syndrome leading to excessive bruising and nosebleeds.

Noonan syndrome leads to delayed puberty in male adolescents and possible infertility related to undescended testes.

Most individuals with Noonan syndrome are of normal intelligence, but a developmental delay is a common symptom. Vision and hearing problems are also potential symptoms.

How does someone get tested for Noonan syndrome?

The initial testing for Noonan syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow. 

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.   

Medical information on Noonan syndrome

The features of classic Noonan syndrome include short stature, congenital heart defects, and facial dysmorphism (broad forehead, hypertelorism, downslanting palpebral fissures, high-arched palate, and low-set, posteriorly rotated ears). Noonan syndrome 1, the most common subtype of Noonan syndrome, is caused by heterozygous mutations in the PTPN11 gene. Noonan syndrome 1 is more often associated with pulmonary stenosis, short stature, bruising, and thorax deformities.

This syndrome was first described by Noonan and Ehmke (1963). The incidence has been estimated to be between 1 in 1000 and 1 in 2500 live births. The gene has been mapped to 12q22 in some families (Jamieson et al., 1994; Brady et al., 1997), however there is evidence for genetic heterogeneity. Tartaglia et al., (2001) found mutations in the PTPN11 gene. This codes for a protein tyrosine phosphatase SHP-2. Mutations were found in more than 50% of Noonan cases. Missense mutations clustered in interacting portions of the amino N-SH2 (Src homology 2) domain and the phosphotyrosine phosphatase domains. Musante et al., (2003) studied 96 cases and found mutations in the PTPN11 gene in 32 (33%). Sarkozy et al., (2003) looked for PTPN11 gene mutations in 71 patients with Noonan syndrome and 13 with multiple lentigenes or Leopard syndrome. Fourteen different PTPN11 mutations were detected in 23 patients with Noonan syndrome and 11 with lentigenes or Leopard syndrome. Pulmonary valve stenosis, most commonly seen in Noonan syndrome, was related to an exon 8 mutation hot spot, while hypertrophic cardiomyopathy, predominant in patients with lentigenes or Leopard syndrome, was associated with mutations in exon 7 and 12. Atrial septal defects were related to exon 3 mutations, while atrioventricular canal defects and mitral valve anomalies were found in association with different exon mutations. Manifestations can be very mild. Zenker et al., (2007) reported a family with a c.1226G to C mutation in exon 11, with clinical, facial features that might not have been recognized as being those of Noonan syndrome.
The main features are short stature, a short neck with webbing or redundancy of the skin, cardiac anomalies (particularly PS, ASD, VSD, PDA and hypertrophic cardiomyopathy - Burch et al., 1993), a characteristic chest deformity with a pectus carinatum superiorly and a pectus excavatum inferiorly, wide spaced nipples and a characteristic facial appearance. The latter changes significantly with age. Left-sided heart lesions including anomalous insertion of the mitral valve, AV canal defects, and sub-aortic obstruction are occasional features (Marino et al., 1995 and Digilio et al., (1997). Coarctation of the aorta may also be a feature in 5-10% on the cases (Digilio et al., 1998). Occasional patients have a restrictive cardiomyopathy (reviewed by Wilmshurst and Katritsis, 1996). Tartaglia et al., (2002) showed that cases with PTPN11 mutations were more likely to have pulmonary stenosis (70% vs. 46%) where as hypertrophic cardiomyopathy was less common in these cases (6% vs. 26%). No mutations in PTPN11 were detected in a group of 24 adults with non-syndromic hypertrophic cardiomyopathy (Sarkozy et al., 2005). Note that some patients might early-on be thought to have mitochondrial disease (Kleefstra et al., 2011).
Nisbet et al., (1999) reported prenatal ultrasound findings in six cases. Abnormalities detected included nuchal fluid, short femora, pleural effusions, hydrops and cardiac and renal anomalies. Achiron et al., (2000) also reported the prenatal findings in Noonan syndrome which in addition included septated cystic hygroma, polyhydramnios and hydrothorax. Joo et al., (2005) reported a woman with Noonan syndrome who gave birth to 3 children with hydrops. A fetus with a massive hygroma colliu, pleural effusion and ascites was found prenatally to have a PTPN 11 mutation by Schluter et al., (2005). These authors suggest that Noonan mutations should be looked for, in those cases with a normal karyotype. In the Lee et al., (2009) report, mutations were found in 16% if those with isolated cystic hygroma. Three fetuses had hydrops.
In the newborn period the main features are hypertelorism, a downward eye slant, low-set posteriorly rotated ears, a deeply grooved philtrum and a broad nasal tip. A history of polyhydramnios is obtained in about 33% of cases and feeding difficulties are present in about 75%.There may be significant feeding difficulties in the first year (Shah et al., 1999). In later infancy the eye slant may become horizontal and the facies can become coarser. In adults the facies may be more subtle. Mild retardation is seen in 35% of cases. 11% of cases need special education (Sharland et al., 1992). Left ventricular thickening can be progressive and may not be present at birth. Growth curves for children with Noonan syndrome are given by Ranke et al., (1988) and Witt et al., (1986) and for adults by Noonan et al., (2003). Fox et al., (2005) reported a single case with cutis verticis gyrata, as did Larsen and Birchall (2007).
Noordam et al., (2001) showed that abnormalities in growth hormone secretion are frequent, but these are not likely to be a significant determinant of short stature in Noonan's syndrome. Thomas and Stanhope (1993) reported their experience of treatment with growth hormone in this condition. Romano et al., (1996) described their experience with growth hormone in 150 children with the condition. They concluded that there was a significant improvement in 42 children monitored for four years. Three out of six boys reached an adult height greater than their pretreatment predicted values. They concluded that it remains uncertain if growth hormone treatment will have a beneficial effect on final stature of Noonan's patients. De Schepper et al., (1997) and Kirk et al., (2001) produced similar findings. Noonan et al., (2003) produce data suggesting that there may be catch up growth in late adolescence although 50% of females and 40% of males had an adult height below the 3rd centile. Elsawi et al., (1994) found that six out of eleven adult males had experienced bilateral testicular maldescent. This was thought to have contributed to delayed puberty, oligozoospermia and raised FSH levels.
A bleeding diathesis can be part of the condition. Sharland et al., (1992) studied 72 affected individuals and found 29 with a prolonged activated partial thromboplastin time with partial factor XI:C, XII:C or VIII:C deficiencies in 36 patients.
Cardio-facio-cutaneous (CFC) syndrome (qv) may be the severe end of the spectrum of this syndrome. Legius et al., (1998) reported a family where some cases had features of CFC syndrome (although relatively mildly). The gene mapped to the Noonan region. Note that keratosis pilaris atrophicans has been reported in classic cases of Noonan syndrome (Pierini and Pierini, 1979).
The mother and son reported by Seaver and Cassidy (1991) have Noonan syndrome, in our opinion.
Lacombe et al., (1992) reported a neonatal case with a 'molluscoid cutaneous excess' over the scalp that resembled cutis verticis gyrata. Ucar et al., (1998) reported a case with features of the condition who had a central giant cell granuloma of the maxillary sinus. Khan et al., (1995) reported a case with a vaginal rhabdomyosarcoma. Lohmann and Gillessen-Kaesbach (2000) reported a case with multiple subcutaneous granular-cell tumours and Yoshida et al., (2008) a case with a hepatoblastoma. Three patients with tumours (a granular cell tumour, an astrocytoma and a Sertoli tumour) were reported by Fryssira et al., (2008). A mixed glioneuronal tumour has also been reported (Sherman et al., 2009).
Schon et al., (1992) reported a case with a large cerebral arteriovenous malformation. Zatare et al., (2014) a case (RAF1 mutation) with neurovascular changes. Hinnant (1995) reported a case with thromboembolic brain infarcts and posterior arterial abnormalities of the brain. Robertson et al., (1997) reported a male infant with the condition who was born with chylothoraces and hepatosplenomegaly and had two episodes of cerebral infarction before the age of six months. Tanaka et al., (1999) reported two unrelated cases with cavernous haemangiomas of the brain. Clinical photographs of the patients were not provided. Moyamoya disease has been reported (Hung et al., 2011).
Cremers et al., (1992) reported a 23-year-old affected man with conductive deafness due to an absence of the long process of the incus. They reviewed the reports of conductive hearing loss in Noonan syndrome from the literature.
Fatourechi et al., (1982) reported a 23-year-old male with Noonan syndrome, obstructive cardiomyopathy and bilateral degenerative chorioretinitis. He also had red hair and an albinoid appearance. Ascaso et al., (1993) reported a 14-year-old girl with keratoconus and optic disc coloboma, however no facial photographs were published. Dollfus et al., (2001), Gravholt et al., (2002) and Carvalho et al., (2003) reported further cases with iridoretinal colobomas.
Maximilian et al., (1992) reported three sibs with the Noonan phenotype but apparently normal parents. In view of the variability of the condition one of the parents could have been a carrier of the gene with minimal expression or a mosaic. Germinal mosaicism was reported by Elalaoui et al., (2010).
Connor et al., (1982) reported an apparent case with multiple odontogenic keratocysts, however this male is now known to have the naevoid basal cell carcinoma syndrome (Fryer, 1993).
Lopez-Miranda et al., (1997) reported a possible case with neuroblastoma, however no clinical photographs were published. A few cases of Noonan with SLE and other autoimmune disorders (thyroiditis) have been reported (Martin et al., 2001, Alanay et al., 2004, Lopez-Rangel et al., 2005).
Wilson et al., (1993) reported a 5-year-old boy with quite convincing features of Noonan syndrome and hypoparathyroidism and T-cell deficiency. He was found to have a deletion of the DiGeorge critical region at 22q11. However Robin et al., (1995) and Digilio et al., (1996) found no real evidence for 22q11 deletions causing Noonan syndrome even when associated with tetralogy of Fallot.
Henn et al., (1997) reported a family where Noonan syndrome seemed to be associated with progressive hydrocephalus. Fryns (1997) reported further cases with this association. In the index case NMR scan revealed agenesis of the corpus callosum and dilation of the 3rd ventricle. The affected mother was normal but her affected brother had massive internal hydrocephalus which included the 4th ventricle. Holder-Espinasse and Winter (2003) reported a case with an Arnold-Chiari malformation.
The authors know of several cases of Noonan syndrome with trimethylaminuria and it is interesting to note the report of Calvert (1973).
de Boode et al., (1996) reported two infants with features of Noonan syndrome, including hypertrophic cardiomyopathy, who were found to have a myopathy. One died in the neonatal period, and one at 10 months. An excess of muscle spindles was found on biopsy of striated muscle. Lethal pulmonary hypertension in 2 neonates was reported by Hopper et al., (2015). Both had the same RAF1 mutation (p.Ser257Leu).
Hasegawa et al., (1996) reported a 12 year old boy with coarctation of the aorta, renal hypoplasia, and some features of Noonan syndrome. They postulated a mutation in a putative lymphogenic gene on the X chromosome that might also be responsible for the Turner phenotype.
Bader-Meunier et al., (1997) reported four apparent cases associated with a myeloproliferative disorder. No further photographs were published. Side and Shannon (1997) suggested that some cases might be a manifestation of NF1 mutations. No photographs were published for the possible case of Noonan syndrome with moyamoya syndrome reported by Ganesan and Kirkham (1997). No photographs were published for the possible case of Noonan syndrome with moyamoya syndrome reported by Ganesan and Kirkham (1997) and another by Yamashita et al., (2004). The patient in this latter report also had antiphospholipid antibodies. Saito et al., (1997) reported a twenty year old girl with severe developmental delay and seizures with features of Noonan syndrome. She was found to have cortical dysplasia of the left temporal lobe together with dilated perivascular spaces. The appearances were suggestive of a neuronal migration defect. An association with leukemia was reported by Pauli et al., (2012), in a patient with a PTPN11 mutation p.E139D.
van der Burgt and Brunner (2000) presented four cases with features of Noonan syndrome, where consanguinity suggested an autosomal recessive form of the disease. In a study of genotype-phenotype correlation (Zenker et al., 2004), it was concluded that PTPN11 mutations were more likely in those with PS, short stature, bruising and thorax deformities. Cardiomyopathy was more common in those without a mutation. Most de novo PTPN11 mutations, are of paternal origin (Tartaglia et al., 2004). Intrafamilial variability, can be extreme (Bertola et al., 2004). A mother and 2 children had the mutation, but only her son was typical. His sister looked very minimally dysmorphic.
A new locus ( 12p12) has now been reported and mutations found in KRAS (Schubbert et al., 2006; Carta et al., 2006). This is the same gene responsible for a significant proportion of juvenile myelomonocytic leukemia (JMML). Some of the patients reported by Schubbert et al., (2006), were compatible with the diagnosis of CFC - see elsewhere, and also the diagnosis in the Carta et al., (2007) cases seems far from certain. Prenatally, Noonan's (with a mutation) can look just like Costello syndrome (Levaillant et al., 2006). In a series of patients with a KRAS mutation, the clinical phenotype ranged from Noonan, to CFC and even Costello syndrome (Zenker et al., 2007).
Another locus, another gene (SOS1) have been identified (Roberts et al., 2007, Tartaglia et al., 2007). Phenotypically, growth is linear and IQ normal., and the emphasis has been on the face and ectoderm (Lepri et al., 2011). There was cardiac disease, pectus, webbed neck, facial keratosis pilaris and curly hair. Two patients reported by Fabretto et al., (2010) with the F6231 SOS1 mutation, had severe respiratory distress (pulmonary lymphangiectasia) and severe feeding problems. Eyebrows are absent and lashes sparse. BRAF mutations, usually associated with CFC, can also cause a Noonan phenotype (Nystrom et al., 2008).
Mutations in NRAS account for only a few situations (Kraoua et al., 2012). Mutations in RIT1 at 1q22 are also causitive (Aoki et al., 2013). Bertola et al., (2014) found 10% of a Brazilian cohort had RIF1 mutations.
Cessans et al., (2016) studied growth patterns in 420 patients with mutations in the PTPN11, SOS1, RAF1, or KRAS genes. Patients with Noonan syndrome were shorter at birth and throughout childhood than the healthy population, with height –2.1 ± 1.2 SDS in adulthood. At birth, patients with PTPN11-related Noonan syndrome were significantly shorter than patients with PTPN11-related Noonan syndrome with multiple lentigines, SOS1, or KRAS.
Pannone et al., (2017) described 16 unrelated individuals with a clinical diagnosis of Noonan syndrome. Five novel missense mutations clustered in the same region and affected residues Leu261, Leu262 and Arg265 of the PTPN11 gene. Most of the patients showed only mild dysmorphic features (a lower prevalence of palpebral ptosis and abnormal/low-set ears), low prevalence of cardiac defects (specifically pulmonary valve stenosis), and low prevalence of short stature. Patients carrying the Arg265 mutation showed no significant cognitive or behavioral issues.

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