Noonan and Ras/Mapk Pathway Syndromes
Short Description or Definition
Noonan syndrome (NS) is a multiple malformation genetic disorder characterized by dysmorphic facies including hypertelorism, ptosis, low-set posteriorly rotated ears, short neck, and relative macrocephaly. Associated features include short stature, chest deformity, undescended testes, muscle hypotonia, frequent learning difficulties, and congenital heart disease most commonly valvular pulmonary stenosis. In 2001 (Tartaglia et al. 2001), a germline mutation in the PTPN11 gene in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway was found to be a cause of nearly 50% of the cases of NS. Since then, a number of other genes in the same pathway have been identified but in about 25% the causative gene for NS has yet to be identified.
Before NS was recognized as a distinct syndrome, some females were misdiagnosed as having Turner syndrome, and many males, given the diagnosis of male Turner, are now recognized as having NS. The recognition of this entity as a distinct new syndrome was presented first in 1963 (Noonan and Ehmke 1963) and then published in 1968 (Noonan 1968). Dr. John Opitz (1985) proposed the eponym “Noonan syndrome” because Dr. Jacqueline Noonan was the first to recognize that the syndrome occurred in both males and females, had normal chromosomes, could be inherited, and frequently had valvular pulmonary stenosis.
NS is the most common of a number of conditions that involve a gene mutation in the RAS/MAPK pathway. These include cardio-facial-cutaneous syndrome, Costello syndrome, Leopard syndrome, and neurofibromatosis1 (NF1).
The estimated incidence of NS is 1:1000–1:2500 births. It occurs worldwide with a slight predominance in males. It is transmitted as an autosomal dominant, but sporadic cases are frequent.
Natural History, Prognostic Factors, and Outcomes
NS may be suspected in fetal life because of the frequent finding of cystic hygroma identified on routine fetal ultrasound. This abnormality is not unique to NS and is not uniformly present. If either parent has NS, and the causative gene is known, prenatal testing of the fetus can be accomplished. There is an increased incidence in polyhydramnios but most newborns are within normal range for length and weight. In a minority of infants with NS, the newborn period may be complicated by significant distress due to pleural effusions with respiratory compromise. Dysmorphic facies may be subtle but the presence of pulmonary stenosis should suggest the possibility of NS. Most cases of NS are not diagnosed in the newborn.
Failure to thrive with poor feeding and vomiting is severe enough in about one quarter of infants to prompt hospitalization for evaluation, and many require treatment for reflux and undergo tube feedings. In the remainder, there may be slower than average motor development with both sitting up and walking somewhat delayed probably attributed to decrease in muscle tone. Speech is often delayed.
Slow growth in early childhood is common with height falling off the growth curve so that by 4–5 years of age, short stature becomes a real concern prompting both a genetic and endocrine evaluation. The majority of children with NS are not recognized until 6–7 years of age. It is important to consider the diagnosis of NS as early as possible so that early intervention can be started. Learning difficulties in school require evaluation of vision and hearing. Both vision problems and hearing loss are relatively common, and early intervention before starting school should be the goal.
The adolescent with NS often feels out of place with peers. Puberty is often delayed so the growth spurt occurring in peers is delayed in NS making the short stature more evident. Although growth hormone deficiency is uncommon in NS, it does occur and an endocrine evaluation is appropriate. Today, there is an increase in the use of growth hormone in NS even without growth hormone deficiency. There is no question that growth hormone treatment will significantly increase growth velocity and also accelerate the usual delay toward puberty. Some feel that growth hormone treatment will increase the estimated adult height but no control study has been carried out to confirm this. For those with very short stature below the third percentile, the addition of 3–4 in. over expected adult height may make daily living activities easier similar to patients with Turner syndrome. The use of growth hormone in all NS patients with more modest short stature is more controversial. Some concerns include the high cost of growth hormone treatment and the message sent that being short is a real handicap and needs treatment. More attention should be given to preparing the NS individual for adulthood. Most patients with NS graduate from high school and many attend college and go on to become teachers, social workers, nurses, and even physicians and lawyers.
The phenotype of NS changes over time (Allanson et al. 1985) and by adulthood many blend into the normal population. The adult with NS has sharper features with a narrow nasal root and a thin bridge. The neck is longer and webbing more prominent and the skin somewhat transparent. It is interesting that more and more adults are being recognized to have NS for the first time after giving birth to an affected child. This is not surprising since there is variation in the overall physical appearance of a NS patient even among affected family members. Both parents should be carefully evaluated when an infant or child is diagnosed with NS. If NS is suspected, this should be confirmed by genetic consultation so parents can be informed of the 50% risk for subsequent offspring.
There is surprising little information on the natural history of NS. Shaw (Shaw et al. 2007) reported a long-term study on 112 NS individuals (age 12–71 years). There were 57 males and 55 females. Mean years of follow-up were 12 years. This study confirmed the need for long-term follow-up of NS patients. The mean age in that study was only 25.3 years and the mean years of follow-up only 12 years. Most patients felt their quality of life was satisfactory or good. A lack of social life and inability to fit in was cited as a problem for some. The only other publication is a report (Noonan 2005a) of 56 patients diagnosed with NS with a range of age 21–59 years. In this report, 12 (23% of 51) reported a diagnosis of depression and were on antidepressant medication. One had a diagnosis of a bipolar disorder and another with oppositional behavior. Two were recovering alcoholics. It was of interest that the majority of the 30 diagnosed in childhood were unmarried (75%), while the 15 diagnosed as adults (85%) were married, and all of those had one to three affected children which had prompted the diagnosis of NS.
Clinical Expression and Pathophysiology
All patients with suspected NS should have a cardiology consultation including an electrocardiogram and echocardiogram. Over 80% of children with NS have some cardiac problem. Valvular pulmonary stenosis is the most common. Fortunately in many, the obstruction is mild and requires only periodic follow-up. Severe pulmonary stenosis may require surgery if the valve is very dysplastic making balloon valvuloplasty unsuccessful. Many with moderate pulmonary stenosis can be treated with cardiac cath. Atrial septal defects are also common and may be isolated or associated with pulmonary stenosis. Nearly every kind of congenital heart disease has been reported. Even with mild lesions, lifelong follow-up is important. Late developments of valvular and vascular disease have been reported. Although hypertrophic cardiomyopathy is present in only 20% of NS patients, there are particular mutations, such as RAF1, with a very high incidence. For the uncommon infant with NS and symptomatic HCM, close follow-up is essential. The development of heart failure in such an infant should prompt early referral for heart transplant evaluation since the mortality is high. For the remainder, regular follow-up is needed, but in many the cardiac status remains stable and asymptomatic for many years.
Many with NS experience easy bruising which may be attributed to a number of coagulation factor deficiencies such as factor XI, XII, and VIII and less commonly factor IX and II. Thrombocytopenia and platelet dysfunction are common. In most, the symptoms are mild but in cases of excessive bruising, epistaxis, menorrhagia, or an anticipated surgical procedure, a hematology consult should be obtained. Aspirin should be avoided. Some infants with NS have enlargement of the liver and spleen which may be due to a myeloproliferative disorder which resembles the highly fatal juvenile myelomonocytic leukemia (e.g., Kratz et al. 2005). Fortunately in NS with a PTPNII mutation, this condition has a favorable prognosis with gradual improvement without specific therapy in the majority of such infants.
Lymphatic problems occur in about 20% and include an increased risk of chylous thorax following cardiac surgery but this condition may occur spontaneously and may be difficult to manage. Both pulmonary lymphangiectasia and intestinal lymphangiectasia are rare findings but peripheral edema often seen in infancy which resolves spontaneously may become a problem in adults. Orthopedic problems such as scoliosis and kyphosis require close follow-up and referral as needed.
Neurologic, cognitive, and behavioral aspects of NS are extremely variable and are still poorly understood. Seizures are not common but occur and are usually responsive to common drug therapy. Arnold-Chiari malformation is uncommon but is increasingly being recognized. Although most individuals with NS have normal intelligence as a group, IQ tends to be ten points lower than unaffected family member or that of the general population (Van der Burgt et al. 1999). There is a difference depending on the gene mutation. SOS1 mutations as a group have normal intelligence and good school performance compared to PTPN11 (Tartaglia et al. 2007) mutations, although specific PTPN11 mutations have no cognitive delay (Cesarini et al. 2009). Muscle weakness results in some clumsiness, and vision may contribute to poor coordination. As a group, they are happy, animated, social, and active children.
Only recently have there been any cognitive, neuropsychological, and behavior studies of NS related to genotype. Pierpont in 2009 (Pierpont et al. 2009) demonstrated that cognitive impairments were common among individuals with a PTPN11 mutation, while all SOS1 individuals had verbal and nonverbal cognitive skills in the normal range. As expected hearing loss, motor dexterity, and parental education levels accounted for significant variability in cognitive outcome. In a more recent paper, Pierpont (Pierpont et al. 2010) studied the language phenotype of children and adolescents with NS. She studied 66 NS patients and found that variation in language skill is closely related to cognitive, perceptual, and motor factors. There was no evidence that specific aspects of language are selectively affected by NS. Venhaeven et al. (2007) reported in 2008 a study of ten NS patients ranging in age from 16 to 59 years. This study confirmed previous studies showing variability in IQ scores but as a whole in the low-average range. In regard to psychoneuroticism, anxiety, and depression, using a study on a self-report instrument (SCL-9o-R) showed higher-than-average results of comorbidity in this population. Conversely, testing on quality of life and satisfaction showed average-to-high satisfaction with different aspects of life. Investigators found the participants as “remarkably friendly, cooperative, and very willing to please.” They found no behavioral phenotype associated with NS but measurements of social cognition and adaptation appeared to be somewhat impaired suggesting some degree of alexithymia is present. This term refers to impaired ability to identify and communicate one’s emotional state. This finding may help explain the report of depression in adult NS patients.
Noonan Syndrome and Autism Spectrum Disorders
It is somewhat surprising that, although NS involves a germline mutation in a pathway playing a major role in brain development, reports of autism in NS are very few. The two cases reported in the literature include a 3-year-old (Ghaziuddin et al. 1994) with a clinical diagnosis of NS but with little details of his appearance provided to confirm a diagnosis of NS although the clinical description of autism is convincing. The second report is of a 13-year-old with a clinical diagnosis of NS (Watanabe et al. 2011) but the physical description given is limited, and no genetic studies were carried out. The description of autism is, however, convincing. A familial case (Tidyman and Rauen 2008) of Leopard syndrome with high-functioning autism spectrum disorder has also been reported, in which a father and three sons with Leopard syndrome all had clinical symptoms consistent with an autism spectrum disorder. Considering the large number of patients with NS from the available published reports, NS would seem to have fewer reports of autism than the general population.
Evaluation and Differential Diagnosis
NS is the most common of a number of conditions due to a gene mutation in the RAS/MAPK pathway (Romano et al. 2010). These include cardio-facial-cutaneous (CFC) syndrome, Costello syndrome (CS), Leopard syndrome (LS), and neurofibromatosis1 (NF1). Cardio-facial-cutaneous (CFC) syndrome, Costello syndrome (CS), and Leopard syndrome (LS) are very rare and may be distinguished by genetic testing. About 10% of patients with NF1 have a Noonan-like phenotype but most of these will demonstrate a neurofibromin deletion. There is considerable similarity in phenotype and associated problems among all these conditions. Gene testing is available. BRAF, MEK1, and MEK2 are the genes in CFC, HRAS in CS, PTPNII and RAF1 in Leopard syndrome, and neurofibromin in NF1. Other syndromes to be considered include Aarskog syndrome, which is caused by an X-linked recessive disorder from a mutation in FGD1 gene; fetal alcohol syndrome, which is caused by maternal alcohol consumption; mosaic trisomy 22, which is characterized by similar facial features but with a chromosomal abnormality; and Turner syndrome, which is characterized by loss of one sex chromosome.
Treatment for NS has been discussed under the various systems affected. Early recognition is essential as appropriate management can be started early. Early genetic evaluation should be sought. Genetic testing can be diagnostic but about 25% of NS patients still have no specific genetic test available. There is a need for additional studies in neuropsychological and behavioral aspects of NS so that the most helpful interventions can be started early. A recent publication (Romano et al. 2010) for the primary care physician on management guidelines in NS has recently been published. NS and the other RAS-MPK disorders have stimulated basic scientists to seek more knowledge of this pathway not only for its role in fetal development and cancer but the role of these mutated genes as we age. There is hope that some of the adverse associations such as postnatal short stature, learning difficulties, and progressive hypertrophic cardiomyopathy may be improved with appropriate genetic therapy. There is still much to learn about Noonan syndrome.
References and Readings
- Noonan, J. A. (2005a). Noonan syndrome. In S. Goldstein & C. R. Reynolds (Eds.), Handbook of neurodevelopmental and genetic disorders in adults (pp. 308–319). New York: Guilford Press.Google Scholar
- Noonan, J. A., & Ehmke, D. A. (1963). Associated noncardiac malformations in children with congenital heart. Journal of Pediatrics, 31, 150–153.Google Scholar
- Van der Burgt, I., Toonen, G., Roosenboom, N., Assman-Hulsmans, C., Gabreels, F., Otten, B., et al. (1999). Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. Journal of Pediatrics, 135(6), 707–713.CrossRefGoogle Scholar