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 (typically appearing during infancy and sometimes progressive) and pulmonary valve stenosis. Postnatal growth restriction 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 centile for age. Sensorineural hearing deficits, present in approximately 20% of affected individuals, are poorly characterized. Intellectual disability, typically mild, is observed in approximately 30% of persons with NSML.

Diagnosis/testing.

The clinical diagnosis of Noonan syndrome with multiple lentigines can be established in a proband with multiple lentigines plus two other cardinal features (cardiac abnormalities; poor linear growth / short stature; pectus deformity; and dysmorphic facial features including widely spaced eyes and ptosis) OR, in the absence of lentigines, three of the other cardinal manifestations plus an affected first-degree relative. The molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in one of four genes (BRAF, MAP2K1, PTPN11, and RAF1).

Management.

Treatment of manifestations: Standard treatment of hypertrophic cardiomyopathy, structural heart defects, eye anomalies / eye movement abnormalities, seizures, cryptorchidism, and developmental issues. Hearing aids may be helpful if hearing loss is present. Growth hormone treatment may be considered for those with short stature, but data on use in NSML are lacking, and growth hormone therapy may be contraindicated in those with hypertrophic cardiomyopathy.

Surveillance: Measurement of growth parameters; cardiac auscultation to assess for new heart murmur; clinical assessment for new neurologic manifestations such as seizures; and monitoring of developmental progress and educational needs at each visit. Annual echocardiogram until age three years and then at ages five years and ten years, or as clinically indicated. Audiology evaluation at least annually in infancy and childhood, or as clinically indicated. Ophthalmology evaluation if eye anomalies or eye movement issues are noted.

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, and certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.

Evaluation of relatives at risk: If the BRAF, MAP2K1, PTPN11, or RAF1 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. If NSML is suspected a cardiology evaluation with echocardiogram is recommended.

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.

Genetic counseling.

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

Suggestive Findings

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
• Family history consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations)
  Note: Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The clinical diagnosis of NSML can be established in a proband based on clinical criteria [Voron et al 1976, Sarkozy et al 2008], or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in one of four genes (BRAF, MAP2K1, PTPN11, and RAF1) listed in Table 1.

Clinical diagnosis

• Multiple lentigines plus two of the other cardinal features, OR
• In the absence of lentigines, three of the other cardinal features plus a first-degree relative with NSML [Sarkozy et al 2008]

Molecular diagnosis. The molecular diagnosis of NSML 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 identified by molecular genetic testing.

Note: (1) Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in one of the genes listed in Table 1 does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, 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 NSML has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, more than 150 individuals with Noonan syndrome with multiple lentigines (NSML) have been reported.

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.
• Neurofibromas have been described but are rare.

Cardiovascular. Approximately 85% of affected individuals have heart defects similar to those observed in Noonan syndrome (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.
• EKG 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. As in Noonan syndrome, facial features may be less evident or more subtle in adults.

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 centile. Postnatal growth restriction resulting in short stature is noted in fewer than 50% of affected individuals, although in most, height is less than the 25th centile for age. Adult height and response to growth hormone therapy have not been studied in this disorder.

Musculoskeletal. Pectus anomalies (either excavatum or carinatum), present in 50% or more of affected individuals, are most often of cosmetic concern only and rarely require medical intervention.

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. Renal anomalies have also (rarely) been reported [Digilio et al 2006].

Eyes. Ophthalmologic involvement in NSML is rare. Described issues include colobomata, stereopsis, and abnormal eye movements [Alfieri et al 2008, Watanabe et al 2011, Van den Heurck et al 2021].

Neurologic. Hypotonia is common in newborns and is associated with psychomotor delays. Seizures and autism spectrum disorder are uncommon manifestations in NSML.

Rare features

• Craniosynostosis. An anecdotal association has been reported between NSML and craniosynostosis, although it is unclear whether this represents a true association or whether the reported individuals had co-occurrence of two conditions. However, it has been postulated that an increased risk of craniosynostosis may be related to the functional link between FGF signaling and the RAS-MAPK pathway [McDonald et al 2018, Rodríguez et al 2019].
  • One reported individual with NSML, who had a pathogenic variant in PTPN11, had sagittal synostosis that required surgical correction as a result of increased intracranial pressure [McDonald et al 2018].
  • A second affected individual, who had a pathogenic variant in RAF1, had multisutural craniosynostosis consistent with a clover-leaf skull that also required surgical correction [Rodríguez et al 2019].
• Malignancies. Hematologic malignancies and other tumors have occasionally been reported in individuals with NSML. However, a review of overall tumor risk in individuals with NSML by Villani et al [2017] noted that the risk is low, such that no routine surveillance for individuals with NSML is recommended. Villani et al [2017] suggested that there be an awareness of a potential risk of malignancy and a low threshold for investigating any signs or symptoms suggestive of malignancy.
  Smpokou et al [2015] reported a total of six individuals with NSML and malignancy:
  • Three individuals had leukemia; all 3 had a germline pathogenic variant in PTPN11 involving amino acid residue 279.
  • One individual had neuroblastoma and one had cerebellar meduloblastoma; both had a germline pathogenic c.1402C>T (p.Thr468Met) PTPN11 variant.
  • One individual with a clinical diagnosis of NSML had a unilateral corneal choristoma.

Genotype-Phenotype Correlations

No genotype-phenotype correlations for BRAF, MAP2K1, or RAF1 have been identified in individuals with NSML.

PTPN11. In contrast to what is observed in Noonan syndrome, the NSML-associated pathogenic variants (see Molecular Genetics) are strongly associated with a predisposition to hypertrophic cardiomyopathy [Tartaglia & Gelb 2010, Gelb et al 2015]. This specific correlation results from a differential impact of NS- and NSML-causing PTPN11 variants on intracellular signalling. In particular, different consequences have been documented on both the MAPK and PI3K-AKT-mTOR pathways [Edouard et al 2010, Marin et al 2011].

Nomenclature

NSML was referred to as cardiomyopathic lentiginosis in the older medical literature. It was also formerly referred to by the acronym LEOPARD syndrome; this designation is no longer considered appropriate.

Prevalence

The population prevalence of NSML is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with NSML, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

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;
• Certain physical activities may be curtailed in order to reduce the risk of sudden cardiac death.

Evaluation of Relatives at Risk

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

• If the BRAF, MAP2K1, PTPN11, or RAF1 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. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended.

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.

Some affected pregnant women may be on medications for their cardiovascular issues. See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search Clinical Trials.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. Note: There may not be clinical trials for this disorder.

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. (Note: Because NSML 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 NSML may have the disorder as the result of a de novo BRAF, MAP2K1, PTPN11, or RAF1 pathogenic variant.
• If the proband is the only family member known to be affected with NSML, recommended evaluations of both parents include:
  • Molecular genetic testing if the NSML-causing pathogenic variant in the proband is known;
  • A thorough physical examination with particular attention to the features of NSML if the NSML-causing pathogenic variant in the proband is not known. If NSML is suspected, a cardiology evaluation with echocardiogram is recommended.
• If the proband has an NSML-related 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 only in the germ cells.
• The family history of some individuals diagnosed with NSML 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 the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband 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 other affected family members.
• If the proband has a known NSML-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If the parents are clinically unaffected (based on appropriate clinical evaluation) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with NSML has a 50% chance of inheriting the NSML-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, members of the parent's family 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.

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.

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).

Prenatal Testing and Preimplantation Genetic Testing

Once the NSML-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

Noonan syndrome with multiple lentigines (NSML) is a RASopathy, a class of disorders for which genetic variation alters proteins belonging to the RAS/mitogen-activated protein kinase (MAPK) signal transduction pathway. The pathogenic variants in PTPN11 that cause NSML are all pathogenic missense variants. These pathogenic variants are distinct from the pathogenic missense variants in PTPN11 that cause Noonan syndrome (NS). The NS-associated pathogenic variants are gain of function, with increased activity of the protein tyrosine phosphatase, SHP-2, encoded by PTPN11. For NSML-associated PTPN11 pathogenic variants, however, the effects are different. The altered SHP-2 proteins have reduced, but not eliminated, phosphatase activities. Biochemical studies have suggested both dominant-negative effects and gain-of-function effects, the latter through liquid-liquid phase separation. Efforts to definitively understand how PTPN11 pathogenic variants cause NSML are ongoing. NS- and NSML-causing PTPN11 pathogenic variants have different effects on the MAPK and PI3k-AKT-mTOR signaling pathways. The other NSML-related genes, BRAF, MAP2K1, and RAF1, encode kinases that phosphorylate proteins in the RAS-MAPK pathway, with positive regulatory functions. The precise mechanism(s) through which alterations in those proteins could mediate NSML have not been well studied.

Cancer and Benign Tumors

Sporadic tumors (including leukemia and solid tumors) occurring as single tumors in the absence of any other findings of NSML may harbor somatic nucleotide variants in BRAF, MAP2K1, PTPN11, or RAF1 that are not present in the germline; thus, predisposition to these tumors is not heritable. See Catalogue of Somatic Mutations in Cancer.

• Solid tumors. BRAF variants mutated in solid tumors, such as p.Asp594Gly and p.Thr599Ile, alter the functional activation segment [Pandit et al 2007]. However, no occurrence of the common BRAF oncogenic somatic p.Val600Glu amino acid substitution has been documented to occur as a germline event associated with cardiofaciocutaneous syndrome (CFCS), NS, or NSML.
• Leukemia. Juvenile myelomonocytic leukemia (JMML) accounts for one third of childhood cases of myelodysplastic syndrome (MDS) and about 2% of leukemia. Somatic pathogenic variants in exons 3 and 13 of PTPN11 have been demonstrated in 34% of a cohort 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 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].

Author Notes

Bruce D Gelb, MD

Mindich Institute for Child Health and Development and the Departments of Pediatrics and Genetics & Genomics, Icahn School of Medicine at Mount Sinai, New York, NY
Email: [email protected]
Web page: icahn.mssm.edu/profiles/bruce-d-gelb

Dr Gelb is trained in pediatric cardiology. His research focuses on understanding the causes and pathogenesis of the RASopathies as well as developing treatments for them. He is a member of the Scientific Advisory Board of RASopathies Network and the Medical Advisory Board of CFC International.

Marco Tartaglia, PhD

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù IRCCS, Rome, Italy
Email: [email protected]

Dr Tartaglia is a molecular geneticist. His research focuses on the molecular bases of human disorders affecting development. He is particularly interested in Noonan syndrome and related disorders, working to identify the genes implicated in these diseases, elucidate the mechanisms underlying pathogenesis, and characterize clinically relevant information for more effective patient care.

Acknowledgments

This work was supported in part by grants from the National Institutes of Health (HL135742) to BDG; Associazione Italiana Ricerca sul Cancro (AIRC, IG21614), European Joint Program on Rare Diseases (NSEuroNet); Lazio Innova (Progetti Gruppi di Ricerca 2020 - Asse I Ricerca e Innovazione); Italian Ministry of Health (Ricerca Corrente); and Italian Ministry of Research (FOE 2019/2020) to MT.

Revision History

• 30 June 2022 (ma) Comprehensive update posted live
• 14 May 2015 (me) Comprehensive update posted live
• 16 November 2010 (me) Comprehensive update posted live
• 30 November 2007 (me) Review posted live
• 13 November 2007 (bdg) Original submission

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