Noonan Syndrome With Multiple Lentigines
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 second and third 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 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 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
- 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 genetic testing approaches can include single-gene testing and use of a multigene panel:
- A multigene panel that includes PTPN11, RAF1, BRAF, MAP2K1, and other genes of interest (see Differential Diagnosis(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 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 variant 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 1 | Proportion of NSML Attributed to Mutation of This Gene | Proportion of Variants Detected by Test Method | |
|---|---|---|---|
| Sequence analysis 2 | Gene-targeted deletion/duplication analysis 3 | ||
| PTPN11 | 90% | Nearly 100% 4 | Unknown, none reported 5 |
| RAF1 | <5% | Nearly 100% 6 | Unknown, none reported 5 |
| BRAF | 2 individuals | See footnote 7 | Unknown, none reported 5 |
| MAP2K1 | 1 individual | See footnote 8 | Unknown, none reported 5 |
| Unknown 9 | ~5% | NA | |
- 1.
See Table A. Genes and Databases for chromosome locus and protein. 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 pathogenic missense variants [Pandit et al 2007].
- 7.
Sequence analysis of all coding exons detected pathogenic missense variants in two individuals with clinical features of NSML [Sarkozy et al 2009, Koudova et al 2009].
- 8.
Sequence analysis of all coding exons detected pathogenic missense variants 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 has been identified [Tartaglia et al 2003a, Tröger et al 2003]. Germline pathogenic variants predominantly in the first and third coding exons of the HRAS proto-oncogene have 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 clinical 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 Clinical Trials.gov in the US and www.ClinicalTrialsRegister.eu 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.