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.

NS is diagnosed on clinical grounds by observation of key features. Affected individuals have normal chromosome studies. Molecular genetic testing identifies a pathogenic variant in PTPN11 in 50% of affected individuals, SOS1 in approximately 13%, RAF1 and RIT1 each in 5%, and KRAS in fewer than 5%. Other reported genes – in which pathogenic variants have been found to cause Noonan syndrome in fewer than 1% of cases – include BRAF, LZTR1, MAP2K1, and NRAS. 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.

Surveillance: Monitoring of anomalies found in any system, especially cardiovascular abnormalities.

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 Noonan syndrome 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 is 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 key features:

• Characteristic facies. The facial appearance of NS shows considerable change with age, being most striking in young and middle childhood, and most subtle in the adult. Key features found irrespective of age include low-set, posteriorly rotated ears with fleshy helices; vivid blue or blue-green irises; and eyes that are often wide-spaced, downslanted, and with epicanthal folds and 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
• Congenital heart defect, 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, inferior pectus excavatum
• Widely set nipples
• Cryptorchidism in males
• Other:
  • Coagulation defects. Coagulation screens (e.g., prothrombin time, activated partial thromboplastin time, platelet count, and bleeding time) 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.
  • Lymphatic dysplasias of the lungs, intestines, and/or lower extremities

Diagnostic criteria developed by van der Burgt in 1997 were published in van der Burgt [2007]. While they have not been used extensively in North America, they are of particular value in the research domain, and are embedded in management guidelines developed by Dyscerne in the United Kingdom [Noonan Syndrome Guideline Development Group 2010]. This clinical management guideline also provides details of recommended baseline investigations and age-specific management. Similar recommendations are provided in Romano et al [2010] and Roberts et al [2013].

Establishing the Diagnosis

The diagnosis of NS is established in a proband with a heterozygous pathogenic variant in one of the genes listed in Table 1 or biallelic pathogenic variants in LZTR1 idenfitied by molecular genetic testing. Testing approaches can include use of a multigene panel, serial single-gene testing, and more comprehensive genomic testing:

• A multigene panel that includes the genes listed in Table1 and other genes of interest (see Differential Diagnosis) is the test of choice for an individual suspected of having Noonan syndrome. Because of significant phenotypic overlap with cardiofaciocutaneous syndrome and Costello syndrome, most available panels include the genes for these diagnoses, too. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Serial single-gene testing can be considered if panel testing is not feasible. Approximately 50% of individuals with NS have a pathogenic missense variant in PTPN11; therefore, single-gene testing starting with PTPN11 would be the next best first test. Appropriate serial single-gene testing if PTPN11 testing is not diagnostic can be determined by the individual's phenotype (e.g., RIT1 if there is hypertrophic cardiomyopathy, SHOC2 if there is a loose anagen hair phenotype, LZTR1 if autosomal recessive inheritance is suspected); however, continued sequential single-gene testing is not recommended as it is more costly than panel testing.
  Since Noonan syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplications have not been reported, testing for intragenic deletions or duplications is unlikely to result in a diagnosis; however, rare cases have been reported for some genes (see Table 1).
• More comprehensive genomic testing (when available) including exome sequencing or genome sequencing may be considered if use of a multigene panel and/or serial single-gene testing fails to confirm a diagnosis in an individual with features of NS.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Prenatal features. Advanced paternal age has been observed in cohorts with simplex NS [Tartaglia et al 2004a]. Common perinatal findings include: polyhydramnios; lymphatic dysplasia including increased nuchal translucency and cystic hygroma; relative macrocephaly; and cardiac and renal anomalies [Myers et al 2014]. In chromosomally normal fetuses with increased nuchal translucency, it is estimated that 5%-15% have PTPN11-associated NS [Bakker et al 2014].

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 [Otten & Noordam 2009]. 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 [Noonan et al 2003].

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, in many affected persons. 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 [Binder et al 2005]. See Management for discussion of growth hormone (GH) treatment.

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 20%-50% of affected individuals; it may be isolated or associated with other cardiovascular defects.
• Hypertrophic cardiomyopathy is found in 20% to 30% 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 and ventricular septal defects, branch pulmonary artery stenosis, and tetralogy of Fallot. Coarctation of the aorta is more common than previously thought [Noonan 2005b].
• 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, or left anterior hemiblock or an RSR' pattern in lead V1 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 [Sharland et al 1992]. 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 2009].

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 [van der Burgt et al 1999, Pierpont et al 2015]. Studies conflict with regard to strength in verbal vs nonverbal performance and no clear pattern has emerged [Lee et al 2005a, Pierpont et al 2009]. 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 2010a].

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, when present, are associated with a higher risk for reading and spelling difficulties [Pierpont et al 2010b]. 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 attention and executive functioning are 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]. Noonan [2005a] has documented problems in a cohort of 51 adults: depression was found in 23%, and occasional substance abuse and bipolar disease was reported. Similar findings were not reported in a large UK cohort followed over many years [Shaw et al 2007].

Detailed psychological assessment of a group of 11 affected individuals identified anxiety, panic attacks, social introversion, impoverished self-awareness, and marked difficulties in identifying and expressing feelings and emotions (alexithymia) [Verhoeven et al 2008]. This same research team suggests that in adulthood mild problems in attention, organizational skills, psychosocial immaturity, and alexithymia may be found, and thus assessment of social cognition and personality may be appropriate [Wingbermuehle et al 2009]. 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% to 80% of males; however, a study of male gonadal function identified Sertoli cell dysfunction in males with cryptorchidism and those with normal testicular descent, suggesting an intrinsic defect leading to hypergonadotropic hypogonadism [Marcus et al 2008].

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, hypertelorism with downslanting 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, hypertelorism, and full or ptotic upper eyelids. The nose has a depressed root, 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.

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].

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.

Prenatal features suggestive of Noonan syndrome, likely of a lymphatic nature, include: transient or persistent cystic hygroma, polyhydramnios, and (rarely) hydrops fetalis [Gandhi et al 2004, Yoshida et al 2004b, Joó et al 2005].

Ocular. Ocular abnormalities including 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].

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, although the true incidence in NS is not known [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). 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.
• 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].
• Overall risk of malignancy. Kratz et al reported on a cohort of 632 individuals with molecularly confirmed NS (inclusive of Noonan syndrome with multiple lentigines) and found four cases of JMML, two of brain tumor, two of ALL, and one neuroblastoma, and 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.
• Myeloproliferative disorders, either transient or more fulminant, can also occur in infants with Noonan syndrome [Kratz et al 2005].
• 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 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.

Genotype-Phenotype Correlations

PTPN11. Analysis of a large cohort of individuals with Noonan syndrome (NS) [Tartaglia et al 2001, Tartaglia et al 2002] has suggested that PTPN11 pathogenic variants are more likely to be found when pulmonary stenosis is present, whereas hypertrophic cardiomyopathy is less prevalent among individuals with NS caused by PTPN11 abnormalities.

Additional cohort analyses have linked PTPN11 pathogenic variants to short stature, pectus deformity, easy bruising, characteristic facial appearance [Yoshida et al 2004a, Zenker et al 2004], and cryptorchidism [Jongmans et al 2004]. In contradistinction, the study of Allanson et al [2010] failed to establish any facial phenotype-genotype correlation.

The presence or absence of a pathogenic variant in PTPN11 does not affect the likelihood of developmental delay, although individuals with the p.Asn308Asp pathogenic variant are said to be more likely to receive normal education [Jongmans et al 2004].

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].

The post-receptor signaling defect causing mild growth hormone resistance in individuals with NS and a PTPN11 pathogenic variant [Binder et al 2005] leads to reduced efficacy of short-term growth hormone (GH) treatment in individuals with a PTPN11 pathogenic variant [Binder et al 2005, Ferreira et al 2005, Limal et al 2006]. However, careful review of height data reveals that individuals with a PTPN11 pathogenic variant presented with more severe short stature and, therefore, reached a lower final height despite a similar height gain [Noordam et al 2008].

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 2004a], 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].

SOS1. Tartaglia et al [2007] concluded that the phenotype in 22 individuals with NS who had an SOS1 pathogenic variant fell within the spectrum of NS, but emphasized the more frequent occurrence of ectodermal abnormalities and a greater likelihood of normal development and stature in these individuals compared to others with NS. In a companion paper, Roberts et al [2007] reported that 14 individuals with NS who had a SOS1 pathogenic variant did not differ in development and stature from other individuals with NS. Cardiac septal defects were found more frequently than in individuals with NS and pathogenic variants in PTPN11. The study did not make specific mention of ectodermal findings.

Pierpont et al [2009] have studied intellectual abilities in Noonan syndrome and report that individuals with SOS1 pathogenic variants generally have average or higher-level skills.

RAF1. Studies emphasize a striking correlation with hypertrophic cardiomyopathy, with 95% of affected individuals with a RAF1 pathogenic variant showing this feature, in comparison with the overall prevalence in NS of 18%. This suggests that pathologic cardiomyocyte hypertrophy occurs because of increased RAS signaling. Multiple nevi, lentigines, and/or café au lait spots were reported in one third of people with RAF1-associated NS.

KRAS. The phenotype associated with pathogenic variants in KRAS tends to be atypical, with greater likelihood and severity of intellectual disability [Zenker et al 2007] in these individuals than in others with NS. Kratz et al [2009] reported the somewhat unusual feature of craniosynostosis in two unrelated probands with NS and a pathogenic missense KRAS variant.

NRAS. Few individuals with an NRAS pathogenic variant have been reported. The clinical features appear to be typical with no particular or distinctive phenotype observed [Cirstea et al 2010].

BRAF, MAP2K1. The rare individuals with a pathogenic variant in BRAF or MAP2K1 also appear to have features of classic Noonan syndrome, albeit with florid ectodermal manifestations [Nava et al 2007, Nyström et al 2008, Sarkozy et al 2009].

RIT1. Compared to the prevalence of hypertrophic cardiomyopathy overall in NS (20%), there is an overrepresentation of HCM in individuals with a pathogenic variant in RIT1 (70%-75%) [Aoki et al 2013, Yaoita et al 2016]. Analysis of affected individuals also suggests a high prevalence of perinatal abnormalities, high birth weight, relative macrocephaly, curly hair, hyperpigmentation, and wrinkled palms and soles but lower prevalence of short stature, pectus deformity, or intellectual disability [Bertola et al 2014, Yaoita et al 2016].

LZTR1. Overall, the features reported in individuals with NS caused by either heterozygous or biallelic pathogenic variants in LZTR1 are those commonly seen in individuals with NS of other genetic causes, including typical facial features, pulmonary valve stenosis, hypertrophic cardiomyopathy, short stature, and developmental delay. A more in-depth evaluation of the phenotype of those with a heterozygous pathogenic variant or biallelic pathogenic variants in LZTR1 suggests increased prevalence of hypertrophic cardiomyopathy in those with biallelic pathogenic variants (19/26 with biallelic pathogenic variants vs 5/26 with a heterozygous pathogenic variant) [Pagnamenta et al 2019].

Penetrance

Penetrance of NS is difficult to determine because of ascertainment bias and variable expressivity with frequent subtlety of features. Many affected adults are diagnosed only after the birth of a more obviously affected infant.

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 (NS), the following evaluations are recommended:

• Complete physical and neurologic examination
• Plotting of growth parameters on NS growth charts
• Cardiac evaluation with echocardiography and electrocardiography
• Ophthalmologic evaluation
• Hearing evaluation
• Coagulation screen to include CBC with differential, PT/PTT (repeat after 12 months if age <12 months at the time