Clinical Diagnosis

The diagnosis of LEOPARD syndrome (LS) is made on clinical grounds, by observation of key features.

Gorlin et al [1969] named the disorder as an acronym alluding to the cardinal features lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.

Additional features occurring frequently in LS:

• Variable degree of cognitive deficits

• Skeletal anomalies

• Hypertrophic cardiomyopathy

Voron et al [1976] proposed diagnostic criteria for LS:

• 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 LS

Testing

Chromosome analysis. Affected individuals have normal chromosome studies.

Molecular Genetic Testing

Genes. PTPN11, RAF1, and BRAF are the genes known to be associated with LS.

Other loci. It is likely that one or more additional, as-yet undefined genes, possibly related to RAS signal transduction, are associated with the 5% of LS cases without PTPN11, RAF1, or BRAF mutations.

Clinical testing

• PTPN11

  • Sequence analysis of coding exons 7, 12, and 13 detects missense mutations in about 90% of individuals tested [Digilio et al 2002, Legius et al 2002, Sarkozy et al 2009].

  • Deletion/duplication analysis. No exonic or whole-gene deletions or duplications involving PTPN11 as causative of LS have been reported. Based on the pathogenetic mechanism, intragenic or whole-gene deletions or duplications are not expected to occur in LS.

• RAF1 

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

  • Deletion/duplication analysis. No exonic or whole-gene deletions or duplications involving RAF1 as causative of LS have been reported. Based on the pathogenetic mechanism, intragenic or whole-gene deletions or duplications are not expected to occur in LS.

• BRAF

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

Table 1. Summary of Molecular Genetic Testing Used in LEOPARD Syndrome

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Gene Symbol	Proportion of LEOPARD Syndrome Attributed to Mutations in This Gene	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
PTPN11	90%	Sequence analysis of select exons (i.e., coding exons 7, 12, and 13) 2	Sequence variants 3	>90%	Clinical
		Sequence analysis	Sequence variants 3	>90%
		Deletion/duplication analysis 4	Exonic or whole-gene deletions 5	Unknown 5
RAF1	<5%	Sequence analysis of select exons (i.e., coding exons 6, 13 and 16) 2	Sequence variants 3 in selected coding exons	>90%	Clinical
		Sequence analysis	Sequence variants 3	>90%
		Deletion/duplication analysis 4	Exonic or whole-gene deletions 5	Unknown 5
BRAF	<5%	Sequence analysis of select exons (i.e., coding exons 6, and 11 to 17) 2	Sequence variants 3 in selected coding exons	>90%	Clinical
		Sequence analysis	Sequence variants 3	>90%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Exons selected for testing may vary among laboratories.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

5. No exonic or whole-gene deletions or duplications involving PTPN11or RAF1 as causative of LEOPARD syndrome have been reported. Based on the molecular mechanisms implicated in disease pathogenesis, exonic or whole-gene deletions or duplications are not expected to cause LS.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband. The diagnosis of LS is made on clinical grounds by observation of key features. Molecular genetic testing can be used to confirm the diagnosis. The following order of testing is recommended:

1.

PTPN11 sequence analysis of coding exons 7, 12, and 13. These exons encompass all the codons of the PTPN11 gene identified to be mutated in LS thus far.

2.

If no mutation is identified, sequence analysis of coding exons 6, 13, and 16 of RAF1 and coding exons 6 and exons 11 to 17 of BRAF.

3.

If no mutation is identified, sequence analysis of the remaining coding exons of PTPN11, RAF1, and BRAF.

Deletion/duplication analysis is not recommended because the mutation detection frequency is unknown.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

The phenotypic overlap that occurs in mutations in genes causing LEOPARD syndrome, Noonan syndrome, and cardiofaciocutaneous syndrome emphasizes that these disorders, previously defined as distinct clinical entities, constitute a phenotypic continuum and yet highlights the usefulness of phenotype-based management:

PTPN11

• Noonan syndrome (NS) (short stature, congenital heart defect, broad or webbed neck, pectus deformities, developmental delay of variable degree, cryptorchidism, and characteristic facies) is an autosomal dominant condition with variable expression. It shows significant overlap with LS, but affected individuals are unlikely to have the profusion of pigmented lesions, lentigines, and café au lait patches or to be deaf. Mutations in exons 2-14 of PTPN11 have been reported in approximately 50% of individuals with NS. These reports confirm that LS and NS are allelic conditions but that particular genotype-phenotype correlations exist with certain mutations in PTPN11 leading to the pigmentary changes and higher prevalence of HCM observed in LS. NS is genetically heterogeneous, with mutations also identified in KRAS, NRAS, SOS1, RAF1, and BRAF (<20% of cases).

• Leukemia and solid tumors. Juvenile myelomonocytic leukemia (JMML) accounts for one third of childhood cases of myelodysplastic syndrome (MDS) and about 2% of leukemia. Mutations in NRAS, KRAS, and NF1 have been shown to deregulate the RAS/MAPK pathway leading to JMML in about 40% of cases. Somatic mutations in exons 3 and 13 of PTPN11 have been demonstrated in 34% of a cohort of individuals with JMML [Tartaglia et al 2003b]. Mutations 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 mutations. All of these mutations cause gain of function in 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 mutations has been extended to include childhood acute lymphoblastic leukemia (ALL). Mutations 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 mutations have been found rarely in solid tumors including breast, lung, and gastric neoplasms and neuroblastoma [Bentires-Alj et al 2004].

• Noonan-like/multiple giant-cell lesion syndrome (NL/MGCLS) is characterized by some cardinal features of NS in association with giant cell lesions of bone and soft tissues (cherubism). PTPN11 mutations have been described in both familial and simplex (i.e., a single occurrence in a family) cases.
  
  Sarkozy et al [2004] reported a girl whose early phenotype was typical of NS but who over time developed the hearing loss and lentigines characteristic of LS. Thus, NL/MGCLS may be too limited and inaccurate a term; a variety of PTPN11 mutations, some of them programming the phenotype of NS and others the phenotype of LS, may also program the development of giant cell lesions.
  
  Overall, NL/MGCLS-associated PTPN11 mutations have been observed in individuals with NS, LS, or cardiofaciocutaneous syndrome (CFCS), including families segregating the trait without any bony involvement. Thus, additional genetic factors may be necessary for the giant cell proliferation to occur. Consistent with this view, this trait is genetically heterogeneous with documented germline mutations affecting other NS/CFCS disease genes coding for transducers participating in the RAS-MAPK signalling pathway [Beneteau et al 2009, Hanna et al 2009, Neumann et al 2009].

RAF1

Noonan syndrome (NS) is also associated with RAF1 germline mutations, with a prevalence ranging between 5% and 15% [Pandit et al 2007, Razzaque et al 2007]. RAF1 mutations underlying NS or LS affect residues clustering in three regions of the protein:

• The N-terminal consensus 14-3-3 recognition sequence (residues 256 to 261) or adjacent residues. Amino acid substitutions within this region account for approximately 70% of all RAF1 mutations.

• Asp486 and Thr491 are residues within the activation segment region of the kinase domain; alterations in these amino acids constitute approximately 15% of RAF1 mutations. Of note, these same amino acids are mutated in the BRAF gene in solid tumors, thereby altering the functional activation segment; in BRAF the mutations are p.Asp594Gly and p.Thr599Ile [Pandit et al 2007].

• Mutation of two adjacent residues (Ser612 and Leu613) account for 15% of RAF1 mutations. These two residues are located at the C-terminus in proximity of Ser621, a residue that undergoes phosphorylation and is important for the regulation of the catalytic activation of RAF1.

• Almost none of the RAF1 residues mutated in NS (and LS) are altered in cancer.

A large percentage (70%-90%) of persons with NS and a RAF1 mutation have hypertrophic cardiomyopathy (HCM), which is significantly lower than the 20% with HCM observed in the general NS population. Moreover, this genotype-phenotype correlation seems to be domain-specific, as HCM appears to be associated with mutations affecting the N-terminal 14-3-3 consensus site or the C-terminus.

BRAF

Cardiofaciocutaneous syndrome (CFCS). Mutations in four genes in the MAPK pathway (BRAF, KRAS, MEK1, and MEK2) have been demonstrated in individuals with CFCS [Niihori et al 2006, Rodriguez-Viciana et al 2006]. BRAF is mutated in 50%-75% of persons with CFCS [Niihori et al 2006, Rodriguez-Viciana et al 2006, Sarkozy et al 2009].

CFCS and LS have similar cardiac findings; however, in CFCS, intellectual disability is usually more severe, with a higher likelihood of structural central nervous system anomalies; more florid skin pathology; and more severe and long-lasting gastrointestinal problems. In CFCS facial appearance tends to be coarser; dolichocephaly and absent eyebrows are more common; and blue eyes are less common.

Analysis of the clinical features of persons with CFCS who are BRAF mutation positive indicated a wide phenotypic variability, although all displayed typical dysmorphic facies, cardiac defects, and skin and skeletal anomalies. Moderate-to-severe intellectual disability, observed in most, is commonly associated with seizures or hypotonia. Pigmentary changes including café-au-lait spots, nevi, and lentigines are common [Niihori et al 2006, Rodriguez-Viciana et al 2006, Sarkozy et al 2009].

Noonan syndrome (NS). BRAF is rarely mutated in NS (~2% of affected individuals) [Sarkozy et al 2009]. The BRAF mutations observed in NS largely do not overlap with those occurring in CFCS, suggesting a genotype-phenotype correlation.

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 LS.

Natural History

Males are more likely than females to be affected with LEOPARD syndrome (LS) [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 LS do not exhibit lentigines.

Café au lait spots 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 LS.

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

Facial features. The facial dysmorphism is similar to that of Noonan syndrome although usually milder [Digilio et al 2006]. Features include inverted triangular-shaped face, downslanting palpebral fissures, low-set posteriorly rotated ears with thickened helices, and hypertelorism. 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 LS. 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. 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 LS. 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 mutations causing LS.

The two RAF1 mutations observed in LS reside in mutational hot spots strongly associated with hypertrophic cardiomyopathy [Pandit et al 2007]. Of note, p.Ser257Leu mutation was associated with both NS and LS [Pandit et al 2007].

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

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

Penetrance

Penetrance of LS 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 LS is not known.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with LEOPARD syndrome (LS), 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 LS 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

• Genetics consultation

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.

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 are recommended.

Testing of Relatives at Risk

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

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

LEOPARD syndrome (LS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with LS have an affected parent.

• A proband with LS may have the disorder as the result of a new gene mutation.

• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, two possible explanations are germline mosaicism in a parent or a 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 mutation include a thorough physical examination with particular attention to the features of LS. Molecular genetic testing of parents is available on a clinical basis if the proband has an identified disease-causing mutation. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of failure by health care professionals to recognize the syndrome and/or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with LS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. (2) If the parent is the individual in whom the mutation first occurred s/he may have somatic mosaicism for the mutation 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 disease-causing mutation 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 LS has a 50% chance of inheriting the mutation.

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

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation, it is likely that the proband has a de novo mutation. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutation of an affected family member must have been identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

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Acknowledgments

This work was supported in part by grants from: the National Institutes of Health (HD001294, HL071207 and HL074728) to BDG and; Telethon-Italy (GGP10020) and European Research Area Network for research programs on rare diseases (E-Rare) 2009 to MT.

Revision History

• 16 November 2010 (me) Comprehensive update posted live

• 30 November 2007 (me) Review posted to live Web site

• 13 November 2007 (bdg) Original submission