Are You Confident of the Diagnosis?

Observed expression of the characteristic phenotypes of LEOPARD syndrome (LS) is extraordinarily variable, making an accurate diagnosis difficult. The minimal criteria that must be met for a diagnosis of LS includes multiple lentigines (Figure 1) and 2 or more of the following: cutaneous abnormalities not including lentigines (cafe noir spots, cafe au lait spots); structural or ECG cardiac conduction abnormalities; pulmonic stenosis; obstructive cardiomyopathy; genitourinary abnormalities (hypospadiasis,cryptorchidism); endocrine abnormalities; neurologic defects (sensorineural deafness, mild learning disabilities); cephalofacial dysmorphism; short stature below the 25th percentile; or skeletal abnormalities (pectus excavatum/carinatum).

Figure 1.

Characteristic lentigines in LEOPARD sydrome, courtesy of Rhonda E. Schnur, MD

In the absence of lentigines, 3 of the previously mentioned areas must be afflicted as well as a first degree relative with a confirmed diagnosis.

What to be alert for in the history
Characteristic findings on physical examination

Children that are suspected of LS have 3 principal traits: characteristic facial features (ocular hypertelorism, broad nasal root, prognathism, or low-set potentially rotated ears), hypertrophic cardiomyopathy (HCM), and café au lait spots (CLS), which occur in 100%, 87%, and 75% of cases, respectively. The most common (90% of LS cases) and noticeable finding on physical examination are lentigines that cover vast areas of skin and are small (between 2mm to 1cm), dark brown, polygonal, and irregularly shaped macules. They can often be seen in the mouth or on the sclerae.

Other cutaneous malformations include onychodystrophy, axillary freckling, localized hypopigmentation, café au lait spots, café noir spots, interdigital webs, and hyperelastic skin. Other systemic abnormalities include mild mental retardation (30%); short stature with 20% of cases below the third percentile after the newborn period; and cephalofacial abnormalities (reported in 35%) with ocular hypertelorism being the most documented (25%).

Further cephalofacial deformities include mandibular prognathism, broad nasal root, dysmorphic skull, low set ears, dental abnormalities, high arched palate, epicanthal folds, ptosis, and corneal tumors. Congenital genitourinary system problems are seen in 26% of patients, primarily males, as well as abnormalities such as cryptorchidism or hypospadias. Various musculoskeletal findings such as pectus excavatum, pectus carinatum, kyphoscoliosis, scapula alata (winged scapula), rib anomalies, and syndactyly are also seen. Dental deformities that are sometimes seen in LS patients include agenesis of adult teeth or hyperdontia.

Expected results of diagnostic studies

Histologic findings indicate that lentigo biopsy specimens have an elevated melanocyte count per unit skin area with prominent rete ridges. Langerhans cells under electron microscopy reveal bulky clusters of melanosomes. Additionally, skin samples in areas lacking pigmentation as well as those pigmented areas contain an increased buildup of melanosomes in LS patients.

Those patients presenting with endocrine dysfunction occasionally show low levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and thyrotropin and elevated levels of 17-hydroxy- and 17-ketosteroids. Genitourinary system evaluation may be facilitated using abdominal ultrasonography or urographic imaging.

To check for pulmonic valve stenosis (PVS), obstructive cardiomyopathy, myxomas, and other structural heart defects, it may be beneficial to perform a transthoracic echocardiogram and an electrocardiogram (ECG), which also may reveal conduction abnormalities such as left axis deviation, prolonged PR intervals, and right bundle branch block. Cranial computed tomography (CT) or magnetic resonance imaging (MRI) may show brain atrophy. To determine the presence of skeletal defects or a bone age assessment, skeletal radiography can be preformed. Sensorineural deafness can be diagnostically confirmed using audiography or auditory evoked potentials.

Noonan syndrome (NS) and Noonan-like/multiple giant cell lesions syndrome present with germinal mutations of the same PTPN11 gene mutated in LS in approximately 40% to 50% of patients. Clinically similar disorders, LS and NS are differentiated molecularly by the disease-causing mutation.

Whereas the mutation in LS causes reduced protein activity, the NS change exemplifies a gain of function mutation. Prenatal distinction between LS and NS can be done but is astonishingly difficult. In a fetus with HCM but a normal karyotype, the leading candidate is LS and needs to be followed with a physical examination of both parents. If a parent has a confirmed case of LS, then protocol dictates obstetric ultrasound at various timings with a fetal ECG in the 20th week of gestation. Genetic tests for the previously mentioned mutations can be done on chorionic villi or amniotic fluid samples.

Other neuro-cardio-facial-cutaneous (NCFC) conditions, such as LS, include NS, neurofibromatosis type 1, Costello syndrome, and cardiofaciocutaneous syndrome. Patients that fall into this group feature facial anomalies, malformed hearts, and growth and mental impairment, in combination with the integumentary, skeletal, and urogenital defects. Differential diagnosis of the individual conditions in this group can be difficult but aided by distinct clinical presentations.

LS has numerous lentigines, café au lait spots, HCM and deafness while NS cases display more obvious facial characteristics in youth and present with PVS as the most common cardiac defect and lack the typical deafness and HCM seen in LS patients. However, it remains difficult to diagnose LS in children who may not initially present with lentigines but then develop them over time. Genetic testing and repeated examinations through the years are essential in suspected cases.

Neurofibromatosis-Noonan syndrome (NFNS) displays clinical overlap with LS. It has the facial and cardiac defects seen in NS, as well as the characteristics of NF1 such as CLS, neurofibromas, CNS and skeletal anomalies. The most conclusive way to differentiate cases from LS is through mutation-based testing.

Turner syndrome, found only in females, can be eliminated from the differential by looking at the patient’s karyotype. Costello syndrome is represented by loose skin folds, intellectual impairment, heart defects, distinguishing facial features, short stature and flexible joints; it is caused by a defect in the HRAS gene.

Who is at Risk for Developing this Disease?

LEOPARD Syndrome (LS) is an extremely rare disorder with no birth prevalence data available. Approximately 200 cases have been documented worldwide; however, LS is potentially underdiagnosed or misdiagnosed since characteristics may be mild. An inaccurate diagnosis may occur due to the absence of lentiginosis. It is often grouped with a collection of disorders known as Ras/MAPK pathway syndromes, and follows Noonan syndrome as the second most likely common NCFC (neuro-cardio-facial-cutaneous) syndrome. The risk for LS is the same for males and females.

What is the Cause of the Disease?

Sporadic or inherited missense mutations to the PTPN11 gene located on chromosome 12q24.1 are responsible for 85% of LS cases. The mutation has full penetrance and an autosomal dominant inheritance pattern. The gene product of PTPN11 is an SRC homology 2-domain-containing ATPase(SHP2) protein. With special emphasis in the Ras/MAPK pathway, SHP2 is a cytoplasmic signaling transducer downstream of multiple receptors for growth factors, hormones, and cytokines. Currently, 11 mutations in exons 7, 12, and 13 have been found in the PTPN11 gene, two of which are responsible for 65% of the reported cases of LS.

Mutations in exons 7 and 12 correlate with a higher incidence of hypertrophic cardiomyopathy (HCM), while those in exon 8 are associated with pulmonary valve stenosis (PVS). Cases in which patients present with HCM lacking a PTPN11 mutation have an increased family history of adverse arrhythmic and nonarrhythmic events such as sudden death, increased left atrial dimensions, and bradyarrhythmias. In those patients with LS that lack a PTPN11 mutation, there is an unusually high incidence of ECG abnormalities secondary to left ventricular hypertrophy (LVH). Exon 13 mutations in the PTPN11 gene are linked to rapidly progressive severe biventricular obstructive HCM with onset during the prenatal period.

As noted, 85% of LS patients have a PTPN11 mutation, and those that lack a PTPN11 mutation will likely have a RAF1 mutation. Approximately 5% of LS cases lack a mutation in both RAF1 and PTPN11. Continued research is still needed to determine how the mutations noted are related to the phenotypical presentations of LS.

There is genetic heterogeneity within LEOPARD syndrome. This has led to the designation of LEOPARD syndrome 2, caused by genetic mutations in the RAF1 gene, and LEOPARD syndrome 3, caused by genetic mutations in the BRAF gene (Table I).

Table I.
Gene Protein Product
PTPN11 Protein tyrosine phosphatase, non-receptor type 11
RAF1 c-Raf
Systemic Implications and Complications

LEOPARD syndrome is a multifocal disease afflicting many different areas. The name of the disorder acts as a mnemonic for remembering the systemic hallmarks of the disease.


Electrocardiographic conduction abnormalities

Ocular hypertelorism

Pulmonary stenosis

Abnormal genitalia

Retarded growth


The characteristic facial dysmorphisms already discussed change with age, going from less to more noticeable. Greater than 80% of patients with LS feature wide set eyes, flat nasal bridge, and dysmorphic ears.

ECG and conduction anomalies are the most common heart defects and occur in 75% and 23% of LS patients, respectively. HCM, which can be congenital, or more often seen in infancy, is the most common of these irregularities of LS and is the only one that is life threatening. It usually affects the left ventricle and obstructs outflow in 40% of cases. HCM onset predates that of multiple lentigines but may worsen in conjunction with it. As noted previously, sudden death has been reported in LS HCM patients.

Diagnostically, a superiorly oriented mean QRS axis in the frontal plane along with other criteria can be used in confirming LS. Pulmonic valve stenosis (PVS) is also seen in many LS patients. Additional cardiac defects or observations seen include prolonged QTc, repolarization abnormalities, mitral valve prolapse, morphologic abnormalities (clefting), atrial/atrioventricular septal defects, coronary artery abnormalities, apical aneurysm, multiple ventricular septal defects, isolated left ventricular enlargement, and endocardial fibroelastosis.

The majority of adults (85%) with LS show growth retardation that is not usually seen at birth. Musculoskeletal anomalies include broad chest, pectus carinatum, mandibular prognathism, winging of the scapulae, scoliosis, and hyperflexibility of the joints. Genital anomalies are mainly cryptorchidism as well as hypospadias and genital hypoplasia. Deafness is common in a quarter of patients and can present at any point in life, but most commonly at birth or during childhood. Delayed psychomotor milestones from hypotonia are commonly seen in newborns, and while mental retardation is rare, learning difficulties are seen in 30% of cases. Tumors are rare but have been seen in patients.

Treatment Options

LS is treated symptomatically and depends on the severity of the anomalies (Table II).

Table II.
Medical Treatment Surgical Procedures Physical modalities
Multiple lentigines: No therapy or Tretinoin cream and hydroquinone cream   Nondrug responsive HCM: removal of outflow obstruction Developmental delays: alternative teaching method
Deafness: hearing Aid
Hypotonia: physical and occupational therapy
HCM: beta blocker or calcium channel blocker PVS with severe valvular dysplasia of the pulmonary valve: valvulotomy or valvulectomy  
Growth retardation: growth hormone injections
Cryptorchidism: hCG injections
Cryptorchidism: orchiopexyHypospadias: hypospadias repair  
  Skeletal deformities: associated surgeries  
  Isolated lentigines: Cryosurgery and laser treatment  

Optimal Therapeutic Approach for this Disease

LS is treated symptomatically and depends on the severity of the anomalies as they present themselves. If not already done, it is important to confirm the diagnosis of LS with a genetic test for a mutation in the PTPN11 or RAF1 gene. Referral to a geneticist is crucial.

The earlier the disease is diagnosed the better, especially to help those children showing signs of mental delay who can benefit from interventional educational support.

Deafness is often seen as an early symptom and should be tested for annually; even though it cannot be cured, it can be treated via a hearing aid. People with profound deafness may benefit from a cochlear implant. Referral to audiology at an early age is important.

For those patients that display low levels of gonadotrophin, which can lead to hypogonadism, sex hormone replacement therapy should be considered. These patients should be followed by an endocrinologist. Cryptorchidism can be detected early and can be treated with hormone therapy and followed with corrective surgery if necessary.

Craniofacial and skeletal surgeries should be obtained if there is need to correct any deformities that may affect the quality of life of the patient.

Patients with mild conduction anomalies have no reason for concern, but those with severe anomalies such as chronic fainting, pulmonary stenosis, HCM, or structural defects can be treated with medications and the appropriate surgical interventions. Due to the fact that cardiovascular defects can be life threatening, all LS patients need lifelong follow-up with cardiology.

Genetic counseling for LS patients is highly recommended, especially for those planning on having families since the disease has an autosomal dominance inheritance pattern. Family members should also be notified and tested if noted symptoms are observed.

Multiple lentigines can be treated at the request of the patient. Success is variable. Topical tretinoin 0.1% cream daily, 4% hydroquinone cream daily, or a combination can be used.

Patient Management

LS is not a fatal disease unless the cardiovascular defects that appear in the disease become severe. Thus, patients should be monitored annually for these defects. Increased awareness should also be given for the noted phenotypical anomalies that occur with the syndrome. Hearing tests should be done annually. Any system that experiences a pathologic change should be monitored for the lifetime of the patient.

These patients should be followed by cardiology, endocrinology, audiology and their primary care physician on a routine basis.

Unusual Clinical Scenarios to Consider in Patient Management

The difficulty of diagnosing LS lies in the variability of the presenting and continuing symptoms. Therefore, it is vital to recognize that the treatment and the management of these patients will be unique to each case depending on the severity of disease. Since there is still no connection with the defected gene and the manifesting traits, it is crucial that other disorders not be completely eliminated. Such disorders include, but are not limited to, Albright syndrome, Carney syndrome, ephelides, lentigo, and neurofibromatosis.

Hyposomia has been reported on rare occasion.

What is the Evidence?

Sarkozy, A, Digilio, MC, Dallapiccola, B. “Leopard syndrome”. Orphanet J Rare Diseases. vol. 3. 2008. pp. 13(A review of LS with full disclosure on presentation, management, treatment, and minor genetic relations. Excellent insights into the phenotypical anomalies in the syndrome.)

Tullu, MS, Muranjan, MN, Kantharia, VC, Parmar, RC, Sahu, DR, Bavdekar, SB. “Neurofibromatosis-Noonan syndrome or LEOPARD Syndrome? A clinical dilemma”. J Postgrad Med. vol. 46. 2000. pp. 98-100. (A comparison of LS with similar presenting disorders and the clinical techniques that can be used to distinguish from these other syndromes or anomalies. Case presentations are excellent in comparing NS and LS.)

Gorlin, RJ, Anderson, RC, Blaw, M. “Multiple lentigines syndrome”. Am J Dis Child. vol. 17. 1969. pp. 652-62. (A classical review of LS with emphasis on clinical presentation and insightful epidemiology relations.)

Voron, DA, Hatfield, HH, Kalkhoff, RK. “Multiple lentigines syndrome. Case report and review of the literature”. Am J Med. vol. 60. 1976. pp. 447-56. (Focused case presentation of LS with guidelines and procedures that help in getting to a diagnosis of a disorder with variable presentations.)

Limongelli, G, Pacileo, G, Marino, B, Digilio, MC, Sarkozy, A, Elliott, P. “Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome”. Am J Cardiol.. vol. 100. 2007. pp. 736-41. (An excellent paper exploring the characteristic cardiovascular anomalies that occur in LS. A wonderful study with data looking into genetic and clinical investigation on 26 patients.)

Sarkozy, A, Conti, E, Digilio, MC, Marino, B, Morini, E, Pacileo, G. “Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome”. J Med Genet. vol. 41. 2004. pp. e68(A thorough series of cases looking at the genetics and clinical manifestations of LS. )

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