Noonan Syndrome

Clinical characteristics.

Noonan syndrome (NS) is characterized by characteristic facies, short stature, congenital heart defect, and developmental delay of variable degree. Other findings can include broad or webbed neck, unusual chest shape with superior pectus carinatum and inferior pectus excavatum, cryptorchidism, varied coagulation defects, lymphatic dysplasias, and ocular abnormalities. Although birth length is usually normal, final adult height approaches the lower limit of normal. Congenital heart disease occurs in 50%-80% of individuals. Pulmonary valve stenosis, often with dysplasia, is the most common heart defect and is found in 20%-50% of individuals. Hypertrophic cardiomyopathy, found in 20%-30% of individuals, may be present at birth or develop in infancy or childhood. Other structural defects include atrial and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Up to one fourth of affected individuals have mild intellectual disability, and language impairments in general are more common in NS than in the general population.

Diagnosis/testing.

The diagnosis of Noonan is established in a proband with suggestive findings and a heterozygous pathogenic variant in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 or either a heterozygous variant or biallelic pathogenic variants in LZTR1 identified by molecular genetic testing. Several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals have been identified.

Management.

Treatment of manifestations: Cardiovascular anomalies in NS are usually treated as in the general population. Developmental disabilities are addressed by early intervention programs and individualized education strategies. Treatment for serious bleeding is guided by knowledge of the specific factor deficiency or platelet aggregation anomaly. Growth hormone (GH) treatment increases growth velocity. Standard treatment for juvenile myelomonocytic leukemia (JMML) and other malignancies, feeding difficulties, ADHD, behavioral problems, cryptorchidism in males, renal anomalies / hydronephrosis, strabismus, hearing loss, and Chiari malformation.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status in infants and toddlers; monitor for evidence of new neurologic manifestations (chronic headache, neck pain, changes in tone, dizziness, or obstructive sleep apnea); monitor developmental progress; assessment of behavioral issues, as age appropriate; skin examination. Annually in childhood or as clinically indicated: ophthalmology and audiology evaluations.

• In children age <5 years: if initial cardiac evaluation is normal, at least annual cardiac evaluations until age 5 years.
• In children age >5 years through adulthood, cardiac evaluation at least every 5 years, or as clinically indicated.
• Prior to any surgical procedure or in those with clinical bleeding: assessment of bleeding history, CBC with differential, and consideration of measurement of coagulation factors.
• For those with pathogenic PTPN11 or KRAS variants: consider physical examination with assessment of spleen size & CBC every 3-6 months until age 5 years to assess for concerns about JMML/malignancy.

Agents/circumstances to avoid: Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis.

Pregnancy management: Consider referral to an adult congenital heart program for peripartum evaluation and management; consider a hematology referral if the affected pregnant woman has a history of bleeding abnormalities and/or has not undergone previous screening for coagulopathy.

Genetic counseling.

NS is most often inherited in an autosomal dominant manner. While many individuals with autosomal dominant NS have a de novo pathogenic variant, an affected parent is recognized in 30%-75% of families. The risk to sibs of a proband with autosomal dominant NS depends on the genetic status of the parents: if a parent is affected, the risk is 50%; when the parents are clinically unaffected, the risk to the sibs of a proband appears to be low (<1%). Each child of an individual with autosomal dominant NS has a 50% chance of inheriting the pathogenic variant.

NS caused by pathogenic variants in LZTR1 can be inherited in either an autosomal dominant or an autosomal recessive manner. The parents of an individual with autosomal recessive NS are typically heterozygotes (i.e., have one LZTR1 pathogenic variant), and may either be asymptomatic or have mild features of NS. If both parents are heterozygous for one LZTR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of having one LZTR1 pathogenic variant (which can be associated with mild NS features), and a 25% chance of being unaffected and not a carrier.

Prenatal testing and preimplantation genetic testing are possible if the NS-related pathogenic variant(s) have been identified in an affected family member.

Suggestive Findings

Noonan syndrome (NS) should be suspected in individuals with the following clinical, laboratory, and family history findings.

Clinical findings

• Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in adulthood. Key features found regardless of age include the following:
  • Low-set, posteriorly rotated ears with fleshy helices
  • Vivid blue or blue-green irises
  • Widely spaced and downslanted palpebral fissures
  • Epicanthal folds
  • Fullness or droopiness of the upper eyelids (ptosis)
  Note: See the National Human Genome Research Institute (NHGRI) Atlas of Human Malformation Syndromes (scroll to ATLAS IMAGES) for photographs of individuals with Noonan syndrome from diverse ethnic backgrounds.
• Short stature for sex and family background
• Congenital heart defects, most commonly pulmonary valve stenosis, atrial septal defect, and/or hypertrophic cardiomyopathy
• Developmental delay of variable degree
• Broad or webbed neck
• Unusual chest shape with superior pectus carinatum and inferior pectus excavatum
• Widely spaced nipples
• Cryptorchidism in males
• Lymphatic dysplasia of the lungs, intestines, and/or lower extremities

Suggestive laboratory findings. Coagulation defects:

• Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and platelet aggregation testing) may show abnormalities.
• Specific testing should identify the particular coagulation defect, such as von Willebrand disease, thrombocytopenia, varied coagulation factor defects (factors V, VIII, XI, XII, protein C), and platelet dysfunction.

Family history is consistent with autosomal dominant (e.g., affected males and females in multiple generations) or ‒ rarely ‒ autosomal recessive inheritance (see Genetic Counseling). Absence of a known family history of Noonan syndrome does not preclude the diagnosis.

Establishing the Diagnosis

The molecular diagnosis of NS is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of the genes listed in Table 1 or biallelic pathogenic (or likely pathogenic) variants in LZTR1.

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis. (3) As up to 20% of individuals meeting the proposed clinical diagnostic criteria [van der Burgt 2007] for NS do not have an identifiable molecular genetic etiology, nondiagnostic genetic testing does not rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing or genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Noonan syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, including those with a clinical and a molecular genetic diagnosis and with an estimated incidence of 1:1000-1:2500, several thousand individuals have been identified with Noonan syndrome (NS) [Roberts et al 2013]. The following description of the phenotypic features associated with this condition is based on these reports.

Prenatal features. Advanced paternal age has been observed in cohorts with simplex NS. Common perinatal findings [Stuurman et al 2019]:

• Polyhydramnios
• Lymphatic dysplasia including increased distended jugular lymphatic sacs, nuchal translucency, cystic hygroma, pleural effusion, and ascites
• Relative macrocephaly
• Cardiac and renal anomalies

In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 3%-15% have PTPN11-associated NS [Stuurman et al 2019].

Growth. Birth weight is usually normal, although edema may cause a transient increase. Infants with NS frequently have feeding difficulties. This period of failure to thrive is self limited, although poor weight gain may persist for up to 18 months.

Length at birth is usually normal. Postnatal growth failure is often obvious from the first year of life [Seo & Yoo 2018]. Mean height then follows the third centile from ages two to four years until puberty, when below-average growth velocity and an attenuated adolescent growth spurt tend to occur. As bone maturity is usually delayed, prolonged growth into the 20s is possible.

Final adult height approaches the lower limit of normal: 161-167 cm in males and 150-155 cm in females. Growth curves have been developed from these cross-sectional retrospective data. One study suggests that 30% of affected individuals have height within the normal adult range, while more than 50% of females and nearly 40% of males have an adult height below the third centile [Seo & Yoo 2018].

In many affected persons, decreased IGF-I- and IGF-binding protein 3, together with low responses to provocation, suggest impaired growth hormone release or disturbance of the growth hormone / insulin-like growth factor I axis. Mild growth hormone resistance related to a post-receptor signaling defect (which may be partially compensated for by elevated growth hormone secretion) is reported in individuals with NS and a PTPN11 pathogenic variant [Seo & Yoo 2018].

Growth hormone (GH) therapy has been used in individuals with NS (see Management):

• In Europe, GH treatment is the standard of care for children with abnormalities of the GH-IGF-I axis and could be used when GH physiology is normal.
• Short- and long-term studies of GH treatment have been published [Ogawa et al 2004, Osio et al 2005, Noordam 2007, Noordam et al 2008, Romano et al 2009, Rohrer et al 2020] and demonstrate a consistent and significant increase in height velocity in children with Noonan syndrome who have been treated.
• The increase in height standard deviation (SD) varies from 0.6 to 1.8 SD and may depend on age at start of treatment, duration of study, age at onset of puberty, and/or GH sensitivity [Seo & Yoo 2018].
• Studies have shown that children with prepubertal NS growth hormone deficiency have increased their growth rate with GH therapy at a rate equivalent to girls with Turner syndrome but at a lower rate than that seen in idiopathic GH deficiency [Lee et al 2015, Zavras et al 2015].

Cardiovascular. Significant bias in the frequency of congenital heart disease may exist because many clinicians have in the past required the presence of cardiac anomalies for diagnosis of NS. The frequency of congenital heart disease is estimated at between 50% and 80%.

• Pulmonary valve stenosis, often with dysplasia, is the most common anomaly in NS, found in 25%-71% of affected individuals; it may be isolated or associated with other cardiovascular defects.
• Hypertrophic cardiomyopathy is found in 10%-29% of individuals with NS. It usually presents early in life: the median age at diagnosis is five months and more than 50% of individuals with NS and hypertrophic cardiomyopathy are diagnosed by age six months [Hickey et al 2011, Wilkinson et al 2012].
• Other structural defects frequently observed include atrial septal defects (4%-57%), ventricular septal defects (1%-14%), atrioventricular canal defects (1%-13%), mitral valve abnormalities (2%-17%), aortic coarctation (2%-9%), patent ductus arteriosus (1%-6%), and tetralogy of Fallot (1%-4%) [Linglart & Gelb 2020].
• An electrocardiographic abnormality is documented in approximately 90% of individuals with NS and may be present without concomitant structural defects. Extreme right axis deviation with superior counterclockwise frontal QRS loop, superior or left axis deviation, left anterior hemiblock, or an RSR' pattern in lead V1 (of no clinical consequence) are common findings [Sharland et al 1992].

Psychomotor development. Early developmental milestones may be delayed, likely in part as a result of the combination of joint hyperextensibility and hypotonia. The average age for sitting unsupported is around ten months and for walking is 21 months [Pierpont 2016]. About 50% of school-age children meet diagnostic criteria for a developmental coordination disorder [Lee et al 2005a] and impaired manual dexterity is significantly correlated with verbal and nonverbal intellectual functioning [Pierpont et al 2015].

Most school-age children perform well in a normal educational setting, but 25% have learning disabilities [Lee et al 2005a] and 10%-15% require special education [van der Burgt et al 1999]. Intellectual abilities are in general mildly lowered in children with NS. IQ scores below 70 are seen in 6%-23% across studies [Pierpont et al 2015]. Studies conflict with regard to strength in verbal vs nonverbal performance and no clear pattern has emerged [Pierpont et al 2015]. There may be a specific cognitive disability, either in verbal or praxic reasoning, requiring a special academic strategy and school placement.

Articulation deficiency is common (72%) but usually responds well to speech therapy. Language delay may be related to hearing loss, perceptual motor disabilities, or articulation deficiencies. The average age at first words is around 15 months and simple two-word phrases emerge on average from age 31 to 32 months [Pierpont et al 2015].

A study of the language phenotype of children and adults with NS showed that language impairments in general are more common in NS than in the general population and a majority of children (70%) receive speech and language therapy. When language issues are present, there is a higher risk for reading and spelling difficulties [Pierpont et al 2015]. Language is significantly correlated with nonverbal cognition, hearing ability, articulation, motor dexterity, and phonologic memory. No specific aspect of language was selectively affected in those with NS.

There is emerging evidence that impairment in attention and executive functioning is one of the most common neuropsychological challenges for children with NS [Pierpont et al 2015]. Studies that rely on screening measures rather than comprehensive diagnostic assessments suggest that children with NS are at heightened risk for autism spectrum disorders; however, further research is needed [Pierpont 2016].

Psychological health. Few details of psychological health in Noonan syndrome are reported. No particular syndrome of behavioral disability or psychopathology is observed, and self-esteem is comparable to age-related peers [Lee et al 2005a]. A study of 37 individuals with a molecular genetic diagnosis of Noonan syndrome demonstrated a higher incidence of emotional dysregulation, irritability, and anxiety symptomatology compared to the general population [Alfieri et al 2021]. Noonan [2005a] documented problems in a cohort of 51 adults: depression was found in 23%, and occasional substance abuse and bipolar disease were reported. Similar findings were not reported in a large UK cohort followed over many years [Shaw et al 2007]. In one study of adults with NS, 49% reported that they had been diagnosed and treated for depression and/or anxiety [Smpokou et al 2012].

Genitourinary. Renal abnormalities, generally mild, are present in 11% of individuals with NS. Dilatation of the renal pelvis is most common. Duplex collecting systems, minor rotational anomalies, distal ureteric stenosis, renal hypoplasia, unilateral renal agenesis, unilateral renal ectopia, and bilateral cysts with scarring are reported less commonly.

Male pubertal development and subsequent fertility may be normal, delayed, or inadequate. Deficient spermatogenesis may be related to cryptorchidism, which is noted in 60%-80% of males; however, a study of male gonadal function identified Sertoli cell dysfunction both in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotropic hypogonadism [Moniez et al 2018].

Puberty may be delayed in females, with a mean age at menarche of 14.6±1.17 years. Normal fertility is the rule.

Facial features. Differences in facial appearance, albeit subtle at certain ages, are a key clinical feature:

• In the neonate, tall forehead, widely spaced eyes with downslanted palpebral fissures, low-set, posteriorly rotated ears with a thickened helix, a deeply grooved philtrum with high, wide peaks to the vermilion border of the upper lip, and a short neck with excess nuchal skin and low posterior hairline are found.
• In infancy, eyes are prominent, with horizontal palpebral fissures, widely spaced eyes, and full or ptotic upper eyelids. The nose has a depressed nasal bridge, wide base, and bulbous tip.
• In childhood, facial appearance is often lacking in affect or expression, as in an individual with a myopathy.
• By adolescence, facial shape is an inverted triangle, wide at the forehead and tapering to a pointed chin. Eyes are less prominent and features are sharper. The neck lengthens, accentuating skin webbing or prominence of the trapezius muscle.
• In the older adult, nasolabial folds are prominent, and the skin appears transparent and wrinkled.

Skeletal features

• Thoracic scoliosis is reported in 13%-30% of individuals diagnosed at a mean age of nine years.
• Estimates of the frequency of the characteristic appearance of the chest (superior pectus carinatum and inferior pectus excavatum with a broad chest and increased inter-nipple distance) range from 28% to 95% [Rodríguez et al 2020].
• Vertebral defects have also been reported.
• Reported upper limb anomalies include cubitus valgus, radioulnar synostosis, brachydactyly, and fifth finger clinodactyly.
• Common maxillofacial features include micrognathia, high arched palate, and dental crowding [Rodríguez et al 2020].
• Small studies have suggested lower bone mineral density in children and osteopenia in adults [Fowlkes et al 2021].
• Multiple giant cell lesions of the jaw, joints (pigmented villonodular synovitis), and/or soft tissue have been reported in association with PTPN11-, SOS1-, and RAF1-associated cases of Noonan syndrome [Miri et al 2018, Rodríguez et al 2020].

Bleeding diathesis. Most persons with NS have a history of abnormal bleeding or bruising. Early studies reported that about one third of all individuals with NS have one or more coagulation defects, with subsequent studies suggesting a lower rate of coagulopathy [Derbent et al 2010]. The coagulopathy may manifest as severe surgical hemorrhage, clinically mild bruising, or laboratory abnormalities with no clinical consequences. A variety of small studies have shown that while 50%-89% of those with NS have either a history of bleeding and/or abnormal hemostatic lab results, only 10%-42% have both (reviewed in Briggs & Dickerman [2012]). A study of 70 individuals with NS who had not had preoperative evaluation for coagulopathy demonstrated a 6.2% risk of perioperative bleeding complications [Briggs et al 2020].

Lymphatic. Varied lymphatic abnormalities are described in individuals with NS. They may be localized or widespread, prenatal, and/or postnatal. Dorsal limb (top of the foot and back of the hand) lymphedema is most common. Less common findings include: intestinal, pulmonary, or testicular lymphangiectasia; chylous effusions of the pleural space and/or peritoneum; and localized lymphedema of the scrotum or vulva.

Ocular. Ocular abnormalities including ptosis, strabismus, refractive errors, amblyopia, and nystagmus occur in up to 95% of affected individuals. Anterior segment and fundus changes are less common. There are case reports of keratoconus and Axenfeld anomaly [Lee & Sakhalkar 2014, Guerin et al 2015, van Trier et al 2018].

Ears/hearing. Hearing impairment has an estimated incidence of 40%. Some individuals have sensorineural hearing loss, others have a secondary conductive hearing loss due to chronic otitis media or middle ear effusion, and some have mixed conductive and sensorineural hearing loss [van Nierop et al 2017].

Dermatologic. Skin differences, particularly follicular keratosis over extensor surfaces and face, are relatively common and may occasionally be as severe as those found in cardiofaciocutaneous syndrome (see Differential Diagnosis).

Café au lait spots and lentigines are described in NS more frequently than in the general population (see Noonan syndrome with multiple lentigines discussion in Genetically Related Disorders).

Other

• Arnold-Chiari I malformation. Eleven cases of Arnold-Chiari malformation have been reported in the medical literature; the true incidence in NS is not known [Smpokou et al 2012, Keh et al 2013, Mitsuhara et al 2014, Zarate et al 2014, Ejarque et al 2015].
• Hepatosplenomegaly is frequent; the cause is likely related to subclinical myelodysplasia.
• Juvenile myelomonocytic leukemia (JMML). The most common hematologic disorder in NS is transient myeloproliferative disorder, typically diagnosed in the neonatal period or early infancy. An estimated 10% of these cases progress to JMML [Niemeyer 2014]. Individuals with Noonan syndrome and a germline pathogenic variant in PTPN11 have a predisposition to this unusual childhood leukemia. In general, JMML in Noonan syndrome runs a more benign course. The associated variants are different from the somatic pathogenic variants in PTPN11-associated JMML, which ‒ when present as germline variants ‒ are associated with neonatal-lethal NS [Mason-Suares et al 2017].
• Other malignancies. One study of individuals with Noonan syndrome caused by a pathogenic variant in PTPN11 supports a threefold increased risk of malignancy [Jongmans et al 2011].
  • Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are found at higher frequency in Noonan syndrome than in the general population [Hasle 2009, Jongmans et al 2011].
  • Solid tumors, such as rhabdomyosarcoma and neuroblastoma, are described [Denayer et al 2010, Jongmans et al 2010]. Three embryonal rhabdomyosarcomas (ERMS) caused by a germline SOS1 pathogenic variant have been reported [Denayer et al 2010, Hastings et al 2010, Jongmans et al 2010]. One with obstructive jaundice involved the biliary ampulla/duodenum; one the bladder; and one the urachus. Three additional cases of ERMS and NS (of the orbit, vagina, and abdomen) were reported; genotype was not determined [Khan et al 1995, Jung et al 2003, Moschovi et al 2007].
  • A recent review of the literature yielded 30 cases of individuals with PTPN11-associated NS yielded 28 cases of brain tumors, 24 of which were low-grade gliomas and glioneuronal tumors [Lodi et al 2020].
• Noonan-like / multiple giant-cell lesion syndrome. The giant-cell granulomas and bone and joint anomalies in Noonan-like / multiple giant-cell lesion syndrome are recognized to be part of the Noonan syndrome spectrum. They can resemble cherubism (an autosomal dominant disorder caused by pathogenic variants in SH3BP2; see Cherubism), lesions observed in neurofibromatosis (see Neurofibromatosis Type 1), or lesions observed in the Ramon syndrome with juvenile rheumatoid arthritis (polyarticular pigmented villonodular synovitis).
  Noonan-like / multiple giant-cell lesion syndrome is caused by pathogenic variants in PTPN11 [Jafarov et al 2005, Wolvius et al 2006] and SOS1 [Beneteau et al 2009, Neumann et al 2009]. One family with Noonan-like / multiple giant-cell lesion syndrome has a PTPN11 pathogenic variant that was also reported in Noonan syndrome without giant-cell lesions [Tartaglia et al 2002]; thus, additional genetic factors may be necessary for the giant-cell proliferation to occur.
• These multiple giant cell lesions are also recognized in persons with cardiofaciocutaneous syndrome, caused by mutation of BRAF and MEK1 [Neumann et al 2009]. Thus, dysregulation of the RAS-MAPK pathway represents the common and basic molecular event predisposing to giant-cell lesion formation, arguing against the existence of Noonan-like / multiple giant-cell lesion syndrome as a separate entity.
• Overall risk of malignancy. Kratz et al [2015] reported on a cohort of 632 individuals with molecularly confirmed NS (inclusive of Noonan syndrome with multiple lentigines) and found four individuals with JMML, two with brain tumor, two with ALL, and one with neuroblastoma; they calculated a childhood cancer standardized incidence ratio of 8.1 [Kratz et al 2015]. Individuals with NS are at an eightfold greater risk of developing a childhood cancer than are those without NS. The overall cancer risk by age 20 years is estimated to be 4% [Lodi et al 2020].
  An international meeting of the American Association for Cancer Research was held to propose consensus surveillance recommendations for RASopathies and other genetic disorders associated with increased childhood cancer risk. Overall, because the cancer risk falls below 5%, routine cancer surveillance was not recommended. However, for those with PTPN11 or KRAS variants known to be associated with myeloproliferative disorder or JMML, physical examination every three to six months with spleen size assessment and complete blood count from birth/time of diagnosis to age five years was recommended for consideration ‒ though there is not yet evidence that this strategy leads to survival advantage [Villani et al 2017].

Phenotype Correlations by Gene

There are no known phenotype correlations for RASA2 or RRAS2.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for BRAF, KRAS, LZTR1, MAP2K1, MRAS, NRAS, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 have been identified.

PTPN11

• Germline pathogenic variants at codons 61, 71, 72, and 76 are significantly associated with leukemogenesis and identify a subgroup of individuals with NS at risk for JMML [Niihori et al 2005].
• Individuals with the p.Asn308Asp pathogenic variant are said to be more likely to receive a typical education [Jongmans et al 2004].
• An in-frame three-nucleotide PTPN11 deletion (p.Gly60del) in a female infant with severe features of Noonan syndrome, including hydrops fetalis and juvenile myelomonocytic leukemia [Yoshida et al 2004], has been reported. The p.Asp61del three-nucleotide PTPN11 deletion has also been reported in a child with typical rather than severe NS [Lee et al 2005b].

Nomenclature

An early term for NS, "male Turner syndrome," incorrectly implied that the condition would not be found in females.

In 1949, Otto Ullrich reported affected individuals and noted a similarity between their features and those in a strain of mice bred by Bonnevie (webbed neck and lymphedema). The term "Bonnevie-Ullrich syndrome" became popular, particularly in Europe.

Prevalence

NS is common and reported to occur in between 1:1,000 and 1:2,500 persons. Mild expression is likely to be overlooked.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Noonan syndrome, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Aspirin therapy should be avoided because it may exacerbate a bleeding diathesis.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

For affected women who are pregnant, consider referral to an adult congenital heart program for peripartum evaluation and management.

Pregnancy is generally a time of increased coagulation, but consider a hematology referral if the pregnant woman has a history of bleeding abnormalities and/or has not undergone previous screening for coagulopathy.

Therapies Under Investigation

The MEK inhibitor trametinib was given under compassionate use to two infants with pathogenic variants in RIT1 and progressive, congenital hypertrophic cardiomyopathy. Trametinib is a highly selective reversible allosteric inhibitor of MEK1/2 activity. In both cases, there was reversal of progressive myocardial hypertrophy and valvar obstruction along with a catch-up pattern of somatic growth [Andelfinger et al 2019].

Dori et al [2020] reported an individual age 14 years with SOS1-related NS who had resolution of mesenteric and retroperitoneal lymphangiectasia and chylothorax after treatment with trametinib, with complete remodeling of the lymphatic system.

Andrew Dauber, MD, Children's National Research Institute, is enrolling children with genetic causes of short stature, including Noonan syndrome, for a vosoritide treatment trial. Vasoritide is a selective NPR-B agonist that targets the growth plate. See Clinical Trials.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Noonan syndrome (NS) caused by pathogenic variants in BRAF, KRAS, MAP2K1, MRAS, NRAS, PTPN11, RAF1, RASA2, RIT1, RRAS2, SOS1, or SOS2 is inherited in an autosomal dominant manner.

NS caused by pathogenic variants in LZTR1 can be inherited in an autosomal dominant or autosomal recessive manner.

Autosomal Dominant Inheritance ‒ Risk to Family Members

Parents of a proband

• 30%-75% of individuals diagnosed with NS have an affected parent. (Note: Because NS is associated with variable expressivity and the manifestations of the disorder are frequently subtle, many affected adults are diagnosed only after the birth of a more obviously affected infant.)
• A proband with NS may have the disorder as the result of a de novo pathogenic variant in an NS-related gene.
• In simplex cases (i.e., those with no known family history), paternal origin of the de novo pathogenic variant has been found universally to date [Yoon et al 2013]. In this cohort, advanced paternal age was observed along with a significant sex-ratio bias favoring transmission to males, a finding that is thus far unexplained.
• If the proband is the only family member known to have NS, recommended evaluations of both parents include the following:
  • A thorough physical examination with particular attention to the features of NS; echo- and electrocardiography; coagulation screening; and examination of photographs of the face at all ages for characteristic features of NS
  • Molecular genetic testing if the NS-causing pathogenic variant in the proband is known
• If the proband has an NS-causing pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with NS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).

Sibs of a proband. The risk to the sibs of a proband depends on the clinical/genetic status of the proband's parents:

• If a parent is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. Because there can be significant intrafamilial variability, sibs may not have the same phenotypic findings as the proband.
• If the parents are clinically unaffected and the proband has an NS-causing pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (germline mosaicism for the PTPN11 c.922A>G pathogenic variant has been reported [Yoon et al 2013]).

Offspring of a proband. Each child of an individual with NS has a 50% chance of inheriting the NS-related pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or is known to have the familial pathogenic variant, the parent's family members may be at risk.

Autosomal Recessive Inheritance ‒ Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for one LZTR1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an LZTR1 pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes may be asymptomatic [Johnston et al 2018] or may have mild features of NS [Jenkins et al 2020].

Sibs of a proband

• If both parents are known to be heterozygous for an LZTR1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting two pathogenic variants and being affected, a 50% chance of inheriting one LZTR1 pathogenic variant and being heterozygous, and a 25% chance of inheriting neither familial pathogenic variant.
• Heterozygotes may be asymptomatic [Johnston et al 2018] or may have mild features of NS [Jenkins et al 2020].

Offspring of a proband. The offspring of an individual with NS are obligate heterozygotes for a pathogenic variant in LZTR1.

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an LZTR1 pathogenic variant.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

High a priori-risk pregnancy

• Molecular genetic testing. Once the NS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
• Ultrasound examination. For a pregnancy at 50% risk, high-resolution ultrasound examination is also possible. Prenatal features are nonspecific but may include polyhydramnios, hydronephrosis, pleural effusion, edema, cardiac defects, distended jugular lymphatic sacs, cystic hygroma, and increased nuchal translucency [Myers et al 2014]. Cystic hygroma may be accompanied by scalp edema, polyhydramnios, pleural and pericardial effusions, ascites, and/or frank hydrops fetalis. The presence of these findings should suggest the diagnosis of NS. In addition, a search for a cardiac defect should be made; congenital heart disease is diagnosed prenatally in about 20% of cases [Myers et al 2014]. Treatment of these pregnancy complications is the same as that in the general population.

Low a priori-risk pregnancy (i.e., a fetus at no known increased risk of NS). Although the ultrasonographic findings described suggest the diagnosis of NS in high-risk pregnancies, they are nonspecific and may be associated with cardiovascular defects or other chromosome and non-chromosome syndromes. In a retrospective analysis of 309 pregnancies with isolated increased nuchal translucency (>99%ile) and no other reported ultrasound findings, four pregnancies were subsequently diagnosed with NS [Pauta et al 2022]. Of 44 pregnancies with nonimmune hydrops fetalis enrolled in the Hydrops-Yielding Diagnostic Results of Prenatal Sequencing (HYDROPS) study, four were diagnosed with NS by trio exome analysis [Al-Kouatly et al 2021].

Molecular Pathogenesis

The genes implicated in Noonan syndrome are part of or interact with the Ras/MAPK pathway. This pathway is a widely important signal transduction pathway. Growth factors, cytokines, hormones, and other extracellular ligands stimulate cell differentiation, proliferation, metabolism, and survival. Adaptor proteins are recruited and form a complex that converts inactive, GDP-bound RAS to its active GTP-bound form. This leads to downstream activation of the RAF-MEK-ERK pathway via sequential phosphorylation, culminating in activated ERK entering the nucleus and altering gene transcription. Noonan syndrome pathogenic variants usually enhance signal flow through this pathway [Roberts et al 2013].

Cancer and Benign Tumors

Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of Noonan syndrome may contain a somatic nucleotide variant in PTPN11, KRAS, LZTR1, MRAS, NRAS, BRAF, or MAP2K1 that is not present in the germline; thus, predisposition to these tumors is not heritable. See Catalogue of Somatic Mutations in Cancer.

• Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of myelodysplastic syndrome (MDS) and about 2% of leukemia. Pathogenic variants in NRAS, KRAS, and NF1 have been shown to deregulate the RAS-MAPK pathway leading to JMML in about 40% of affected individuals. Somatic pathogenic variants in exons 3 and 13 of PTPN11 have been demonstrated in 34% of individuals with JMML in one cohort [Tartaglia et al 2003, Tartaglia et al 2004, Hasle 2009].
• Pathogenic variants in PTPN11 exon 3, were also found in 19% of children with MDS with an excess of blast cells, which often evolves into acute myeloid leukemia (AML) and is associated with poor prognosis. Nonsyndromic AML, especially the monocyte subtype FAB-MD, can be caused by PTPN11 pathogenic variants. These pathogenic variants cause a gain of function in tyrosine-protein phosphatase non-receptor type II (SHP-2), likely leading to an early initiating lesion in JMML oncogenesis with increased cell proliferation ‒ attributable in part to prolonged activation of the RAS-MAPK pathway.
• The spectrum of leukemogenesis associated with PTPN11 pathogenic variants has been extended to include childhood acute lymphoblastic leukemia (ALL). Pathogenic variants were observed in 8% of individuals with B-cell precursor ALL, but not among children with T-lineage ALL [Tartaglia et al 2004]. Additionally, Bentires-Alj et al [2004] described SHP-2-activating PTPN11 pathogenic variants in solid tumors including breast, lung, and gastric neoplasms and neuroblastoma.
• Somatic RAF1 nucleotide variants have only rarely been found in cancer; most of these cancer-causing variants do not cluster in the regions that are germline mutational hot spots in Noonan syndrome [Pandit et al 2007].
• NRAS variants are commonly observed in somatic cancer; they occur in regions different from germline NRAS variants that cause Noonan syndrome.
• MAP2K1 somatic variants have been reported in ovarian cancer [Estep et al 2007] and lung cancer [Marks et al 2008].
• Somatic SOS1 pathogenic variants have not been found in cancer.
• Recent studies have identified somatic RIT1 pathogenic variants in lung adenocarcinoma and myeloproliferative or mixed myelodysplastic/myeloproliferative neoplasms [Berger et al 2014, Cancer Genome Atlas Research Network 2014].
• The somatic p.Gly248Arg pathogenic variant in LZTR1 has been identified in melanoma, glioblastoma, and colorectal cancers (COSMIC database).

Author Notes

Amy E Roberts, MD, FACMG

Department of Cardiology and Division of Genetics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA

Email: amy.roberts@cardio.chboston.org

Website: www.childrenshospital.org/directory/amy-roberts

Dr Roberts is trained in both clinical genetics and pediatrics. Her research focuses on genotype phenotype correlations and gene discovery in Noonan syndrome and other RASopathies. She is a member of the Scientific Advisory Board of RASopathies Network and the Medical Advisory Board of CFC international.

Acknowledgments

Our understanding of Noonan syndrome is deeply informed by the life's work of the late Dr Jacqueline A Noonan [Gelb et al 2020], who first described the diagnosis in 1963. The author would like to acknowledge the original author of this GeneReview, Judith Allanson, and the mentorship, collaboration, and collegiality of leaders in the field, including Bruce Gelb, Bryan Hall, Maria Kontaridis, Raju Kucherlapati, Mary Ella Pierpont, Rene Pierpont, Alicia Romano, Marco Tartaglia, Ineke van der Burgt, and Martin Zenker. Finally, Dr Roberts would like to thank the leadership of the RASopathies Network and Noonan Syndrome Foundation as well as the many families with Noonan syndrome who have shared their children's experiences in clinic, in research, and at family meetings for their selflessness and advocacy without which much of this work would not have been possible.

Author History

Judith E Allanson, MD; Children's Hospital of Eastern Ontario (2001-2021)

Amy E Roberts, MD (2001-present)

Revision History

• 17 February 2022 (aa) Revision: encephalocraniocutaneous lipomatosis added to Genetically Related Disorders
• 16 December 2021 (ma) Comprehensive update posted live
• 8 August 2019 (ma) Revision: pathogenic variants in LZTR1 associated with autosomal dominant and autosomal recessive Noonan syndrome
• 25 February 2016 (ha) Comprehensive update posted live
• 4 August 2011 (me) Comprehensive update posted live
• 7 October 2008 (me) Comprehensive update posted live
• 6 September 2007 (cd) Revision: mutations in RAF1 associated with Noonan syndrome
• 22 December 2006 (cd) Revision: SOS1 mutations responsible for some cases of Noonan syndrome; clinical testing available
• 22 May 2006 (cd) Revision: prenatal testing for Noonan syndrome caused by KRAS mutations clinically available
• 16 May 2006 (cd) Revision: KRAS testing clinically available
• 1 May 2006 (ja) Revision: mutations in KRAS cause Noonan syndrome
• 9 March 2006 (me) Comprehensive update posted live
• 17 December 2003 (me) Comprehensive update posted live
• 15 November 2001 (me) Review posted live
• 2 August 2001 (ja) Original submission

Published Guidelines / Consensus Statements

• Noonan Syndrome Guideline Development Group. Management of Noonan syndrome – a clinical guideline (pdf). University of Manchester: DYSCERNE. Available online. 2010. Accessed 6-7-23.
• Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013;381:333-42. [PubMed]
• Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, Roberts AE, Robinson W, Takemoto CM, Noonan JA. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010;126:746-59. [PubMed]

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