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Leopard Syndrome

Bridget E. McIlwee, DO and Warren W. Piette, MD



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  • LEOPARD syndrome is a genetically heterogeneous syndrome caused by a mutation in one of three distinct genes, causing LEOPARD syndrome 1, 2, or 3.

  • LEOPARD is an acronym for the constellation of cardinal features that characterize the disease:

    • L: lentigines (often appear during childhood; progress to thousands of brown-black macules by adolescence; mucosa is spared). >90% of patients (but not all) have lentigines. Café au lait spots may also be present (70–80%).

    • E: ECG conduction abnormalities (heart defects in 85%, including hypertrophic cardiomyopathy [HCM], which typically appears in infancy and may be progressive)

    • O: ocular hypertelorism (50%)

    • P: pulmonic valve stenosis (this and HCM are most common structural cardiac abnormalities)

    • A: abnormalities of male genitalia (particularly cryptorchidism)

    • R: retardation of growth (postnatal, in <50%; less common in LEOPARD syndrome than in related RAS-opathies)

    • D: sensorineural deafness in 20% (poorly characterized as a manifestation of LEOPARD syndrome; typically mild) (1)

  • One of a group of disorders called the neurocardiofaciocutaneous syndromes (NCFCS)

  • Synonym(s): Literature most firmly supports LEOPARD syndrome (LS); formerly known as progressive cardiomyopathic lentiginosis, familial multiple lentigines syndrome, lentiginosis profusa syndrome, Gorlin syndrome II, Capute-Rimoin-Konigsmark-Esterly-Richardson syndrome, Moynahan syndrome


  • LEOPARD acronym based on a constellation of clinical features observed in 1969: multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern (2)

  • PTPN11 mutations in >80% of LS patients (3)


  • Penetrance is high but difficult to quantify due to ascertainment bias and variable expressivity. Often, the diagnosis is made in an adult only after the diagnosis of a more severely affected child.

  • When a child of apparently unaffected parents is diagnosed with LS, consider genetic testing for parents and other 1st-degree relatives. Nonpenetrance, nonpaternity, or undisclosed adoption may explain apparently sporadic cases.

  • No clear racial predilection

  • Predominant sex: male > female, possibly due to ascertainment bias


Unknown prevalence in the United States and internationally 

General Prevention

Prenatal diagnosis or preimplantation genetic testing is possible in families when the disease-causing mutation is known. An unknown percentage of cases are due to de novo mutations. 

Etiology and Pathophysiology

  • LEOPARD syndrome and a related disorder, Noonan syndrome (NS), are allelic disorders resulting from different missense mutations. 90% of these mutations are in the PTPN11 gene.

  • The PTPN11 gene product, tyrosine phosphatase, participates in the transduction of intracellular signals essential for diverse developmental processes, including cardiac development.

  • Melanocytic hyperplasia resulting in lentigines is postulated to result from abnormal neural crest cell development.

  • Increased β-adrenergic effector activity in the myocardium has been shown on histology.

  • Electron microscopic examination of lentigines shows large accumulations of melanosomes containing giant granules of pigment, similar to those found in café au lait spots in neurofibromatosis.


  • Genetically heterogeneous syndrome caused by one of three different genes

  • Autosomal dominant with high penetrance and highly variable expressivity

  • Unknown percentage of cases due to new mutations

  • LEOPARD syndrome 1 (LS1, OMIM #151100) is caused by mutation in the PTPN11 gene on chromosome 12q24.

    • 90% of LS is caused by PTP11 mutations.

    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 7, 12, or 13).

    • LEOPARD syndrome 1 is allelic to Noonan syndrome 1 (NS1; OMIM 163950).

    • LS mutations are dominant-negative mutations that interfere with growth factor/ERK-MAPK–mediated signaling; NS mutations are activating.

    • LS and NS mutations are located in different exons of this gene.

  • LEOPARD syndrome 2 (LS2, OMIM #611554) is caused by mutation in the RAS1 gene on chromosome 3p25.2.

    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 6, 13, or 16).

    • LS2 is allelic to Noonan syndrome 5 (NS5; OMIM #611553).

  • LEOPARD syndrome 3 (LS3, OMIM #613707) is caused by mutation in the BRAF gene on chromosome 7q34.

    • >90% of these mutations are detectable by sequence analysis (especially sequence variants of exons 6 and 11–17).

    • LS3 is allelic to Noonan syndrome 7 (NS7; OMIM 613706).

Commonly Associated Conditions

  • Variable cognitive deficits: intellectual disability (usually mild) in 30%

  • Skeletal abnormalities

  • Hypertrophic cardiomyopathy

  • Malignant melanoma

  • Risk of malignancy in LS is no greater than in the general population.


  • Diagnosis is made on clinical grounds and may be confirmed by molecular genetic testing. Many features develop during puberty or later in life, which may delay diagnosis.

  • Must have lentigines plus two cardinal features OR, in the absence of lentigines, must exhibit three cardinal features plus one 1st-degree relative diagnosed with LS

  • Cardinal features are lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.

  • Generally a clinical diagnosis, but if suspected in young children, confirmation by genetic testing is appropriate.

  • Other associated findings that are not cardinal features but should increase suspicion for LS:

    • Other cutaneous abnormalities:

      • Axillary freckling

      • Interdigital webbing

      • Café au lait spots

      • Localized hypopigmentation

      • Hyperelastic skin

      • Onychodystrophy

    • Other genitourinary abnormalities such as hypospadias

    • Endocrine abnormalities:

      • Low follicle-stimulating hormone, luteinizing hormone, thyrotropin

      • Elevated 17-hydroxy and 17-ketosteroids

    • Neurologic defects:

      • Seizures

      • Nystagmus

      • Hyposmia

    • Cephalofacial dysmorphisms:

      • Mandibular prognathism

      • Broad nasal root

      • Dysmorphic skull

      • Low-set ears

      • High palate arch

      • Epicanthal folds

      • Ptosis

      • Corneal tumors

    • Other skeletal abnormalities:

      • Pectus excavatum or carinatum

      • Kyphoscoliosis or winging of scapulae

      • Syndactyly

      • Delayed development or agenesis of permanent or supernumerary teeth

Note: These features are recognized as minor manifestations of this complex and highly variable syndrome


  • Family history of cardiac arrhythmias, or abnormalities of skin pigmentation

  • 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 (1) but may not be present before age 4–5 years, may darken with age, and number in the thousands by puberty.

Physical Exam

  • Complete physical and neurologic examination

  • Skin: multiple lentigines of face, neck, and upper torso, sparing mucosa: dispersed, flat brown-black macules numbering in the thousands by puberty; café au lait spots, hyperelastic skin

  • Cardiovascular: conduction abnormalities, pulmonary valve stenosis

  • Height: postnatal growth retardation; plot growth on Noonan syndrome growth charts (4)

  • Skeletal examination: pectus excavatum or carinatum, kyphoscoliosis, syndactyly, careful assessment of spine and ribs

  • HEENT: characteristic facial features similar to those of Noonan syndrome (although less prominent), inverted triangle face shape, downslanting palpebral fissures, ocular hypertelorism, ptosis, broad nasal root, high-arched palate, low-set posteriorly rotated ears

  • Ophthalmologic examination

  • GU: abnormalities of genitalia, especially cryptorchidism, hypospadias

Differential Diagnosis

  • Noonan syndrome: characterized by short stature, congenital heart defects, webbed neck, pectus deformities, variable developmental delay, cryptorchidism, and characteristic facial features; also autosomal dominant with variable expressivity; NS shares features of LS, but individuals with NS do not typically have lentigines, café au lait spots, or deafness.

  • Ephelides (freckles)

  • Lentigo

  • Neurofibromatosis

  • Carney syndrome: multiple familial neoplasia and lentiginosis syndrome associated with Carney complex gene 1, a PRKAR1A gene on 17q22–24

  • Albright syndrome

  • Cardiofaciocutaneous syndrome

  • Turner syndrome

  • Watson syndrome: phenotypically similar to neurofibromatosis 1

  • Costello syndrome: shares features of LEOPARD, Noonan, and cardiofaciocutaneous syndromes but lacks PTPN11 mutation

  • Williams syndrome

Diagnostic Tests & Interpretation

  • Molecular genetic testing is informative in approximately 90% of individuals who meet clinical criteria for LEOPARD syndrome.

  • Molecular diagnostic testing strategy to confirm (or establish) diagnosis of LS in a proband

    • PTPN11 sequence analysis of coding exons 7, 12, and 13. No causative mutations (for LS) have been identified in any other exons.

    • If no mutation is identified in PTPN11, perform sequence analysis of coding exons 6,13, and 16 of RAF1 and coding exons 6 and 11–17 of BRAF.

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

  • Approximately 10% of individuals with LS do not have identifiable PTPN11, RAF1, or BRAF mutations. It is likely that other as-yet unidentified genes related to RAS signal transduction may be implicated in these cases.

Diagnostic Procedures/Other

  • ECG (especially before any surgical procedure), echocardiography; consider Holter monitoring.

  • Hearing evaluation: age-appropriate assessment of auditory acuity (may include auditory brainstem response [ABR], auditory steady-state response [ASSR], pure tone audiometry); audiovestibular testing

  • Radiographic assessment of spine and rib cage if clinically indicated

  • Developmental assessment

  • Renal ultrasound or urographic examination, especially in males or those with known urologic abnormalities, urinalysis

  • MRI of brain and cervical spine if neurologic symptoms are present


Most patients are able to live normal lives and have a normal lifespan. Treatment of individual manifestations as in the general population 
  • Cardiovascular abnormalities

  • Cryptorchidism

  • Hearing loss: hearing aids, education for hearing impaired, cochlear implant if appropriate

  • Developmental disability: early intervention and individualized educational plan

  • Histology of a lentigo biopsy demonstrates hyperpigmentation of the basal membrane, with increased numbers of melanocytes and slight acanthosis and diffuse lymphohistiocytic infiltrate with some scattered melanophages (5).


  • Lentigines

    • Tretinoin cream or hydroquinone cream to help lighten lesions

    • Cryotherapy or laser therapy may be impractical due to large number of lesions.

  • Structural cardiac anomalies

    • β-Adrenergic receptor blockers or calcium channel blockers for outflow tract obstruction as appropriate

  • Arrhythmias: appropriate antiarrhythmics (5)

Additional Therapies

Treatment of manifestations: 
  • Hearing loss: hearing aids, education for hearing impaired, sign language; consider cochlear implantation.

  • Developmental disabilities: early intervention, individualized education planning

Issues for Referral

  • Cardiology: dysrhythmias, cardiomyopathy

  • Genetics: genetic counseling

  • Urology: genital abnormalities

  • Audiology:, sensorineural deafness

  • Dermatology lentigines of cosmetic concern, or lesions suspicious for malignancy

Ongoing Care

  • Management of individuals with LEOPARD syndrome is based on the phenotype rather than on the molecular diagnosis per se.

  • Cardiac conduction abnormalities merit special attention.

  • Monitor lentigines for appearance of malignant melanoma or nevocellular nevi; incidence increases with increasing number of lentigines.

Follow-up Recommendations

  • Developmental evaluation and follow-up

  • Hearing loss: twice-yearly exams and routine audiometry to assess degree of loss

  • Cardiology for conduction abnormalities, cardiomyopathy, structural heart disease, as appropriate

  • Dermatology: surveillance of lentigines

  • Endocrinology, as indicated

Patient Education


Gelb  BD, Tartaglia  M. LEOPARD syndrome. In: Pagon  RA, Adam  MP, Ardinger  HH, et al, eds. Gene Reviews. Seattle, WA: University of Washington; 1993–2014.
Gorlin  RJ, Anderson  RC, Blaw  ME. Multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern. Am J Dis Child.  1969;117(6):652–662. [View Abstract]
Ogata  T, Yoshida  R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev.  2005;2(4):669–674. [View Abstract]
Witt  DR, Keena  BA, Hall  JG, et al. Growth curves for height in Noonan syndrome. Clin Genet.  1986;30(3):150–153. [View Abstract]
Martínez-Quintana  E, Rodríguez-González  F. LEOPARD syndrome: clinical features and gene mutations. Mol Syndromol.  2012;3(4):145–157. [View Abstract]

Additional Reading

  • Porciello  R, Divona  L, Strano  S, et al. LEOPARD syndrome. Dermatol Online J.  2008;14(3):7. [View Abstract]



  • L81.4 Other melanin hyperpigmentation

  • Q82.4 Ectodermal dysplasia (anhidrotic)


  • 709.09 Other dyschromia

  • 757.31 Congenital ectodermal dysplasia


  • 111306001 Multiple lentigines syndrome

  • 45167004 Moynahan’s syndrome

  • 402777004 hereditary lentiginosis (disorder)

Clinical Pearls

  • LEOPARD syndrome is an autosomal dominant genetic disorder, typically a clinical diagnosis that may be confirmed by genetic testing.

  • Clinical diagnosis requires a high degree of clinical suspicion.

  • Management of individuals with LEOPARD syndrome is based on the phenotype.

  • Diagnostic criteria:

    • Lentigines plus two cardinal features

    • In the absence of lentigines, three cardinal features (plus one 1st-degree relative diagnosed with LS)

  • Typically, not all features will be present in each patient.