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Noonan Syndrome with Multiple Lentigines

Synonyms: LEOPARD Syndrome, Multiple Lentigines Syndrome

, MD and , PhD.

Author Information
, MD
Departments of Pediatrics and Genetics and Genomic Sciences
Mindich Child Health and Development Institute
Icahn School of Medicine at Mount Sinai
New York, NY
, PhD
Dipartimento di Ematologia, Oncologia e Medicina Molecolare
Istituto Superiore di Sanità
Rome, Italy

Initial Posting: ; Last Update: May 14, 2015.

Summary

Clinical characteristics.

Noonan syndrome with multiple lentigines (NSML) is a condition in which the cardinal features consist of lentigines, hypertrophic cardiomyopathy, short stature, pectus deformity, and dysmorphic facial features, including widely spaced eyes and ptosis. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase to the thousands by puberty. Some individuals with NSML do not exhibit lentigines. Approximately 85% of affected individuals have heart defects, including hypertrophic cardiomyopathy (HCM) (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth retardation resulting in short stature occurs in fewer than 50% of affected persons, although most affected individuals have a height that is less than the 25th percentile for age. Sensorineural hearing deficits, present in approximately 20%, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.

Diagnosis/testing.

The diagnosis of NSML is established either by clinical findings or, if clinical findings are insufficient, by identification of a heterozygous pathogenic variant in one of four genes (PTPN11, RAF1, BRAF, and MAP2K1) by molecular genetic testing. At least one additional gene in which mutation is causative is likely to exist.

Management.

Treatment of manifestations: Treatment of cardiovascular anomalies and cryptorchidism is the same as in the general population. Treatment of hearing loss includes hearing aids, enrollment in an educational program for the hearing impaired, and consideration of cochlear implantation. Developmental disability is managed by early intervention programs and individualized education strategies.

Prevention of secondary complications: For individuals with hypertrophic cardiomyopathy, certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.

Surveillance: Periodic follow up and often lifelong monitoring may be necessary for any abnormality, especially a cardiovascular abnormality. For hearing loss, twice-yearly examination by a physician familiar with hereditary hearing impairment and repeat audiometry to confirm the stability of the hearing loss are recommended. Routine monitoring of developmental progress and linear growth in childhood and adolescence.

Agents/circumstances to avoid: For individuals with hypertrophic cardiomyopathy, treatment with growth hormone must be undertaken with great caution, if at all, to avoid exacerbating a cardiac condition.

Pregnancy management: Affected women with hypertrophic cardiomyopathy or valve dysfunction may be at risk for development or exacerbation of heart failure during pregnancy; cardiac status in these women should be monitored, especially during the 2nd and 3rd trimesters of pregnancy.

Genetic counseling.

NSML is inherited in an autosomal dominant manner. A proband with NSML may have the disorder as the result of new gene mutation; the proportion of cases caused by de novo mutation is unknown. Each child of an individual with NSML has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in an affected family member is known.

Diagnosis

Suggestive Findings

Noonan syndrome with multiple lentigines (NSML) should be suspected in individuals with one or more of the following cardinal features:

  • Lentigines
  • Cardiac abnormalities, particularly hypertrophic cardiomyopathy
  • Poor linear growth/short stature
  • Pectus deformity
  • Dysmorphic facial features, including widely spaced eyes and ptosis

Additional features occurring frequently in NSML:

  • Variable degree of cognitive deficits
  • Sensorineural hearing loss
  • Cryptorchidism
  • Skeletal anomalies
  • Café-au-lait macules

Establishing the Diagnosis

The diagnosis of Noonan syndrome with multiple lentigines is established either clinically in a proband with the following clinical findings or, if clinical findings are insufficient, by identification of a heterozygous pathogenic variant in one of four genes (PTPN11, RAF1, BRAF, and MAP2K1) by molecular genetic testing (see Table 1).

Clinical findings

Molecular genetic testing approaches can include single-gene testing and use of a multi-gene panel.

  • A multi-gene panel that includes PTPN11, RAF1, BRAF, MAP2K1, and other genes of interest (see Differential Diagnosis). Note: The genes included and sensitivity of multi-gene panels vary by laboratory and over time.
  • Serial single-gene testing of PTPN11, RAF1, BRAF, and MAP2K1 based on the order in which a pathogenic variant is most likely to be identified. Although gene-targeted deletion/duplication analysis could be considered, the mutation detection frequency is unknown and expected to be extremely low.

Table 1.

Summary of Molecular Genetic Testing Used in Noonan Syndrome with Multiple Lentigines

Gene 1Proportion of NSML Attributed to Mutation of This GeneProportion of Variants Detected by Test Method
Sequence analysis 2Gene-targeted deletion/duplication analysis 3
PTPN1190%Nearly 100% 4Unknown, none reported 5
RAF1<5%Nearly 100% 6Unknown, none reported 5
BRAF2 individualsSee footnote 7Unknown, none reported 5
MAP2K11 individualSee footnote 8Unknown, none reported 5
Unknown 9~5%NA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

4.

Most pathogenic variants causing NSML are identified in exons 7, 12, and 13 [Digilio et al 2002, Legius et al 2002, Sarkozy et al 2009].

5.

No exon or whole-gene deletion or duplication involving PTPN11or RAF1 has been reported as causative of NSML. Based on the molecular mechanisms implicated in disease pathogenesis, exon or whole-gene deletions or duplications are not expected to cause NSML.

6.

Sequence analysis of coding exons 6, 13, and 16 detects all reported missense mutations [Pandit et al 2007].

7.

Sequence analysis of all coding exons detected missense mutations in two individuals with clinical features of NSML [Sarkozy et al 2009, Koudova et al 2009].

8.

Sequence analysis of all coding exons detected missense mutations in one individual with clinical features of NSML [Nishi et al 2015].

9.

It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with the ~5% of individuals with NSML in whom no pathogenic variant has been identified in PTPN11, RAF1, or BRAF.

Clinical Characteristics

Clinical Description

Males are more likely than females to be affected with Noonan syndrome with multiple lentigines (NSML) [Voron et al 1976], either as a result of bias of ascertainment or preferential survival of affected male fetuses, as proposed for Noonan syndrome (NS) [Tartaglia et al 2004a].

Dermatologic. Multiple lentigines present as dispersed flat, black-brown macules, mostly on the face, neck, and upper part of the trunk with sparing of the mucosa. In general, lentigines do not appear until age four to five years but then increase into the thousands by puberty [Coppin & Temple 1997]. Some individuals with NSML do not exhibit lentigines.

Café au lait macules are also observed in up to 70%-80% of affected individuals [Digilio et al 2006], usually preceding the appearance of lentigines.

Skin hyperelasticity has also been described.

Cardiovascular. Approximately 85% of affected individuals have heart defects, which are similar to those observed in NS but with different frequencies [Limongelli et al 2007].

Hypertrophic cardiomyopathy is detected in up to 70% of individuals with heart defects (compared to 25% in NS). It most commonly appears during infancy and can be progressive.

Pulmonary valve stenosis is noted in approximately 25% of affected individuals. Abnormalities of the aortic and mitral valves are also observed in a minority of persons with NSML.

ECG abnormalities, aside from those typically associated with hypertrophic cardiomyopathy, include conduction defects (23%).

Facial features. Dysmorphic facial features are similar to those seen in Noonan syndrome, although usually milder [Digilio et al 2006]. Features include inverted triangular-shaped face, downslanted palpebral fissures, low-set posteriorly rotated ears with thickened helices, and widely spaced eyes. The neck can be short with excess nuchal skin and a low posterior hairline.

Hearing. Sensorineural hearing deficits are present in approximately 20% of persons with NSML. Minimal information is available about the progression of deafness in those with milder degrees of hearing impairment.

Growth. Birth weight is usually normal but may be above the 97th percentile. Postnatal growth retardation resulting in short stature is noted in fewer than 50% of affected individuals, although most have a height that is less than the 25th percentile for age. Issues such as adult height and response to growth hormone therapy have not been studied in this disorder.

Psychomotor development. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML. Specific information concerning the deficits typically found in these children is not available.

Genitourinary. Cryptorchidism, unilateral or bilateral, is present in approximately one third of affected males. Other abnormalities including hypospadias, urinary tract defects, and ovarian abnormalities are observed infrequently.

Genotype-Phenotype Correlations

No clear-cut genotype-phenotype correlations have been observed among the PTPN11 pathogenic variants causing NSML.

The two RAF1 pathogenic variants observed in NSML (see Table 3) reside in mutational hot spots strongly associated with hypertrophic cardiomyopathy [Pandit et al 2007]. Of note, the p.Ser257Leu pathogenic variant was associated with both NS and NSML [Pandit et al 2007].

In addition to NSML in two persons, one third of persons with NS and a RAF1 pathogenic variant had other findings including multiple nevi, lentigines, and/or café-au-lait spots, suggesting a predisposition to hyperpigmented cutaneous lesions associated with these pathogenic variants.

Koudova et al [2009] reported a person with NSML and normal intelligence who had a novel sequence change in BRAF, further illustrating that the phenotypic spectrum caused by BRAF pathogenic variants is broader than previously assumed and does not always include intellectual disability.

Nomenclature

Noonan syndrome with multiple lentigines (NSML) was referred to as cardiomyopathic lentiginosis in the older medical literature.

Until recently, NSML was referred to as LEOPARD syndrome but this name is being phased out due to objections from some families with affected children who found the term offensive.

Penetrance

Penetrance of NSML is difficult to determine because of ascertainment bias and variable expressivity, frequently with subtlety of phenotypic features. Affected adults may be diagnosed only after the birth of a more obviously affected infant.

Prevalence

The population prevalence of NSML is not known.

Differential Diagnosis

Turner syndrome, found only in females, is distinguished from Noonan syndrome with multiple lentigines (NSML) by demonstration of an X-chromosome abnormality on cytogenetic studies. The characteristic facial features are also distinct, and in Turner syndrome renal anomalies are more common, developmental delay is much less frequently found, and left-sided heart defects are the rule.

The Watson syndrome (OMIM 193520) phenotype also overlaps with that of neurofibromatosis type 1 and the two are now known to be allelic. Variably present in both Watson syndrome and NSML are short stature, pulmonary valve stenosis, variable intellectual development, and skin pigment changes including café au lait macules. Lentigines are not described in Watson syndrome. Heterozygous pathogenic variants in NF1 are causative.

Costello syndrome (CS) shares features with NSML, NS, and CFCS. Two series of individuals with CS have been studied molecularly and no PTPN11 pathogenic variant has been identified [Tartaglia et al 2003a, Tröger et al 2003]. Germline mutation occurring predominantly in the first and third coding exons of the HRAS proto-oncogene has been shown to cause CS [Aoki et al 2005].

Other. NSML should be distinguished from other syndromes with developmental delay, short stature, congenital heart defects, and distinctive facies, especially Williams syndrome.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Noonan syndrome with multiple lentigines (NSML), the following evaluations are recommended:

  • Complete physical and neurologic examination
  • Plotting of growth parameters on Noonan syndrome growth charts by Witt et al [1986] (Specific growth charts for NSML are not available.)
  • Cardiac evaluation with echocardiography and electrocardiography
  • Ophthalmologic evaluation
  • Hearing evaluation including complete assessment of auditory acuity using age-appropriate tests (e.g., ABR testing, auditory steady-state response [ASSR] testing, pure tone audiometry)
  • Renal ultrasound examination; urinalysis if urinary tract abnormalities are identified
  • Clinical and radiographic assessment of spine and rib cage
  • Brain and cervical spine MRI if neurologic symptoms are present
  • Multidisciplinary developmental evaluation
  • Consultation with a medical geneticist and/or genetic counselor

Treatment of Manifestations

Treatment of cardiovascular anomalies and cryptorchidism is usually the same as in the general population.

Treatment of hearing loss may include the following:

  • Fitting with appropriate hearing aids
  • Enrollment in an appropriate educational program for the hearing impaired
  • Consideration for cochlear implantation, a promising habilitation option for persons with profound deafness
  • Recognition that, as distinct from many clinical conditions, the management and treatment of severe-to-profound congenital deafness involves primarily the social welfare and educational systems rather than the medical care system [Smith et al 2005]

Any developmental disability should be addressed by early intervention programs and individualized education strategies.

Treatment of cryptorchidism in males is usually the same as in the general population.

Prevention of Secondary Complications

For individuals with hypertrophic cardiomyopathy, certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.

For individuals diagnosed in infancy, early intervention may limit the extent of intellectual and developmental disabilities.

Surveillance

If anomalies are found in any system, periodic follow up should be planned and lifelong monitoring may be necessary, especially of cardiovascular abnormalities.

For hearing loss, twice-yearly examination by a physician familiar with hereditary hearing impairment and repeat audiometry to confirm the stability of the hearing loss is recommended.

Surveillance for intellectual and developmental disabilities as per routine pediatric care is of particular importance due to the higher prevalence of these issues in individuals with NSML.

Surveillance for growth delay as per routine pediatric care is important due to the higher prevalence of poor linear growth in affected children.

Agents/Circumstances to Avoid

For individuals with hypertrophic cardiomyopathy, treatment with growth hormone must be undertaken with great caution, if at all, to avoid exacerbating a cardiac condition.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures.

  • If the PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, a thorough physical examination with particular attention to the features of NSML may clarify the disease status of at-risk relatives.

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

Pregnancy Management

For affected women, cardiac status should be monitored during pregnancy. Those with hypertrophic cardiomyopathy or valve dysfunction may be at risk for the development or exacerbation of heart failure during pregnancy, especially during the second and third trimesters.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Noonan syndrome with multiple lentigines (NSML) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with NSML have an affected parent.
  • A proband with NSML may have the disorder as the result of a de novo PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include a thorough physical examination with particular attention to the features of NSML.
  • The family history of some individuals diagnosed with NSML may appear to be negative because of failure to recognize the disorder in family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations and molecular genetic testing has been performed on the parents of the proband

Note: If the parent is the individual in whom the pathogenic variant first occurred s/he may have somatic mosaicism for the pathogenic variant and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

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

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with NSML has the pathogenic variant, the PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant is likely de novo. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal 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.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the PTPN11, RAF1, BRAF, or MAP2K1 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • RASopathiesNet
    244 Taos Road
    Atlandena CA 91001
    Phone: 626-676-7694
    Email: lisa@rasopathies.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    Suite 2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • Children's Heart Foundation
    PO Box 244
    Lincolnshire IL 60069-0244
    Phone: 888-248-8140 (toll-free); 847-634-6474
    Fax: 847-634-4988
    Email: info@childrensheartfoundation.org
  • CongenitalHeartDefects.com
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Noonan Syndrome with Multiple Lentigines: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Noonan Syndrome with Multiple Lentigines (View All in OMIM)

151100LEOPARD SYNDROME 1; LPRD1
164757V-RAF MURINE SARCOMA VIRAL ONCOGENE HOMOLOG B1; BRAF
164760V-RAF-1 MURINE LEUKEMIA VIRAL ONCOGENE HOMOLOG 1; RAF1
176872MITOGEN-ACTIVATED PROTEIN KINASE KINASE 1; MAP2K1
176876PROTEIN-TYROSINE PHOSPHATASE, NONRECEPTOR-TYPE, 11; PTPN11
611554LEOPARD SYNDROME 2; LPRD2
613707LEOPARD SYNDROME 3; LPRD3

PTPN11

Gene structure. The gene has 15 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 2. Missense mutations in PTPN11 were identified in 90% of individuals with Noonan syndrome with multiple lentigines (NSML) examined. Pathogenic variants alter residues at or close to the N-SH2/PTP interacting surfaces, which are involved in switching between active and inactive conformations of the protein, and participating in catalysis. Biochemical characterization of a panel of mutants documented that NSML-associated pathogenic variants impair catalytic activity [Hanna et al 2006, Kontaridis et al 2006, Tartaglia et al 2006].

Table 2.

Selected PTPN11 Pathogenic Allelic Variants of Interest Including Those Causing Noonan Syndrome with Multiple Lentigines

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.836A>Gp.Tyr279CysNM_002834​.3
NP_002825​.3
c.836A>Cp.Tyr279Ser
c.1381G>Ap.Ala461Thr
c.1391G>Cp.Gly464Ala
c.1403C>Tp.Thr468Met
c.1492C>Tp.Arg498Leu
c.1493G>Tp.Arg498Trp
c.1517A>Cp.Gln506Pro
c.1528C>Gp.Gln510Glu

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. PTPN11 encodes tyrosine-protein phosphatase non-receptor type 11 (also known as protein tyrosine phosphatase non-receptor type 11, or SHP-2), a widely expressed intracellular protein. The protein is a key molecule in the cellular response to growth factors, hormones, cytokines, and cell adhesion molecules [Neel et al 2003]. It is required in several intracellular signal transduction pathways that control diverse developmental processes (including cardiac semilunar valvulogenesis and blood cell progenitor commitment and differentiation) and has a role in modulating cellular proliferation, differentiation, migration, and apoptosis. The protein has two tandemly arranged SRC-homology 2 (SH2) domains at the N-terminus (N-SH2 and C-SH2), a single catalytic protein tyrosine phosphatase (PTP) domain, and a C-terminal tail with two tyrosyl phosphorylation sites and a proline-rich stretch. The N-SH2-PTP interaction maintains the protein in an inactive state.

Abnormal gene product. Aberrant function of SHP-2 causes dysregulation of growth factor and cytokine-mediated RAS/ERK/MAPK and PI3K/AKT signal flow, perturbing cell proliferation [Fragale et al 2004, Chan et al 2005, Keilhack et al 2005, Hanna et al 2006, Kontaridis et al 2006].

Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of childhood cases 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 cases. Somatic pathogenic variants in exons 3 and 13 of PTPN11 have been demonstrated in 34% of a cohort of individuals with JMML [Tartaglia et al 2003b]. Pathogenic variants in 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-M5, has been shown to be caused by PTPN11 pathogenic variants. All of these pathogenic variants result in a gain of function of the protein tyrosine phosphatase non-receptor type 11 (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 B-cell precursor ALL cases, but not among children with T-lineage ALL [Tartaglia et al 2004b]. Additionally, SHP-2-activating PTPN11 pathogenic variants have been found rarely in solid tumors including breast, lung, and gastric neoplasms and neuroblastoma [Bentires-Alj et al 2004].

RAF1

Gene structure. RAF1 comprises 17 exons. It has three conserved regions (CR): CR1, encoded by exons 2-5, contains a RAS-binding domain (RBD) and a cysteine-rich domain (CRD); CR2 is encoded by exon 7; CR3, encoded by exons 10-17, contains the kinase domain and its regulatory element, the activation segment. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. See Table 3. The consensus 14-3-3 recognition site includes residues Arg256, Ser257, Ser259, and Pro261, and is encoded by exon 7 (coding exon 6). One pathogenic variant identified in NSML (p.Ser257Leu) altered this CR2 domain, interfered with 14-3-3 binding, and caused greater kinase activity than wild-type protein, both basally and after stimulation [Pandit et al 2007].

The other NSML-associated pathogenic variant, p.Leu613Val, altered the C-terminal portion of RAF1 (coding exon 16). This pathogenic variant also caused greater kinase activity than wild-type protein, both basally and after EGF stimulation.

Table 3.

RAF1 Pathogenic Allelic Variants of Interest Including Those Causing Noonan Syndrome with Multiple Lentigines

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.770C>Tp.Ser257LeuNM_002880​.2
NP_002871​.1
c.1837C>Gp.Leu613Val

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. RAF1 is ubiquitously expressed and encodes a protein of 648 amino acids with three domains. CR1 contains a Ras-binding domain; CR2 is a site of regulatory phosphorylation and association with the 14-3-3 protein. CR1 and CR2 both have negative regulatory function, removal of which results in oncogenic activity. The kinase domain, CR3, also associates with 14-3-3.

The protein is highly regulated with numerous serine and threonine residues that can be phosphorylated, resulting in activation or inactivation. The serine at residue 259, which is in CR2, is particularly important. In the inactive state, the N-terminus of RAF1 interacts with and inactivates the kinase domain at the C-terminus. This conformation is stabilized by 14-3-3 protein dimers that bind to phosphorylated Ser259 and Ser261. Dephosphorylation of Ser259 facilitates binding of RAF1 to RAS-GTP and propagation of the signal through the RAS-MAPK cascade via RAF1 MEK kinase activity.

Abnormal gene product. NSML-associated RAF1 pathogenic variants increase and prolong RAS downstream signaling through enhanced kinase activity, leading to increased activation of MAP kinase kinases (MAP2K1 and MAP2K2).

RAF1 cancer and benign tumors. Almost none of the RAF1 residues mutated in NS (and NSML) are altered in cancer.

BRAF

Gene structure. The gene has 18 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Two germline missense changes affecting exon 6 have been reported in two persons with a diagnosis of NSML (see Table 4) [Koudova et al 2009, Sarkozy et al 2009].

Table 4.

BRAF Pathogenic Allelic Variants Causing Noonan Syndrome with Multiple Lentigines

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.721A>Cp.Thr241ProNM_004333​.4
NP_004324​.2
c.735A>Tp.Leu245Phe

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Exons 3-6, encode a RAS-binding domain (RBD) and a cysteine-rich domain (CRD), while the kinase domain is encoded by exons 11-17. BRAF is ubiquitously expressed and encodes a protein of 766 amino acids. It is activated following GTP-bound RAS binding, and phosphorylates and activates the dual specificity mitogen-activated protein kinase kinases (MAP2K1 and MAP2K2).

Abnormal gene product. The NSML-associated p.Thr241Pro BRAF pathogenic variant enhances RAS signaling through increased activation of MEK and ERK kinases [Sarkozy et al 2009]. NIH-3T3 cell colony focus formation assay data indicate that associated (p.Thr241Pro) BRAF mutants do not confer enhanced transformation to cells [Sarkozy et al 2009].

BRAF cancer and benign tumors. BRAF variants mutated in solid tumors (p.Asp594Gly and p.Thr599Ile) alter the functional activation segment [Pandit et al 2007].

Note: No occurrence of the common BRAF oncogenic somatic p.Val600Glu amino acid substitution has been documented to occur as a germline event associated with CFCS, NS, or NSML.

MAP2K1

Gene structure. The gene has 11 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. One germline missense mutation affecting exon 2,the variant c.305A>G (p.Glu102Gly), has been reported in one subject with a diagnosis of NSML (see Table 5) [Nishi et al 2015].

Table 5.

MAP2K1 Pathogenic Allelic Variants of Interest Including Those Causing Noonan Syndrome with Multiple Lentigines

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequence
c.199G>Ap.Asp67AsnNM_002755.3
NP_002746.1
c.305A>Gp.Glu102Gly

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. Exon 2 encodes the N-terminal portion of the catalytic domain. The gene is widely expressed and encodes a protein of 393 amino acid residues. MAP2K1 is a dual specificity protein kinase. It is activated following phosphorylation by kinases of the RAF family, and phosphorylates and activates the mitogen-activated protein kinases (MAP1K1 and MAP1K2).

Abnormal gene product. The NSML-associated p.Glu102Gly MAP2K1 variant has not been characterized biochemically or functionally, but is predicted to enhance signaling through the MAPK cascade.

References

Literature Cited

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Chapter Notes

Acknowledgments

This work was supported in part by grants from: the National Institutes of Health (HL071207) to BDG; and Telethon-Italy (GGP13107), Associazione Italiana Ricerca sul Cancro (AIRC, IG13360) and Ministry of Health (RF-2011-02349938) to MT.

Revision History

  • 14 May 2015 (me) Comprehensive update posted live
  • 16 November 2010 (me) Comprehensive update posted live
  • 30 November 2007 (me) Review posted to live Web site
  • 13 November 2007 (bdg) Original submission
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