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Dermatology > INTERNAL MEDICINE
LEOPARD Syndrome
Article Last Updated: Jul 20, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Sergiusz Jozwiak, MD, PhD, Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland
Sergiusz Jozwiak is a member of the following medical societies: Sigma Xi
Coauthor(s):
Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Medicine, Professor of Pediatrics, Professor of Pathology, Professor of Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Editors: James J Nordlund, MD, Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio; Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
cardiocutaneous lentiginosis syndrome, multiple lentigines syndrome, generalized lentiginosis, centrofacial lentiginosis, lentiginosis profusa syndrome, lentiginosis-deafness-cardiopathy syndrome, cardiocutaneous syndrome, progressive cardiomyopathic lentiginosis, Moynahan syndrome, (OMIM 151100)
Background
LEOPARD syndrome is a complex dysmorphogenetic disorder of variable penetrance and expressivity. Gorlin et al introduced the acronym LEOPARD as the name of the syndrome in 1969 to recall the main features of the disorder.
- Lentigines (multiple)
- Electrocardiographic conduction abnormalities
- Ocular hypertelorism
- Pulmonary stenosis
- Abnormalities of genitalia
- Retardation of growth
- Deafness
Not all of the findings are present in any given patient. Zeisler and Becker first described the syndrome in 1936 in a 24-year-old woman with progressive generalized lentigines, hypertelorism, pectus carinatum, and prognathism. The first familial cases were reported in twins by Rosen and subsequently in 8 persons from a large 3-generation pedigree reported by Pipkin. Subsequent communications added new findings in isolated patients or families. Moynahan first documented the association of the syndrome with cardiac abnormalities and short stature in 1962.
Pathophysiology
Recent molecular studies proved that LEOPARD syndrome and Noonan syndrome are allelic disorders caused by different missense mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at band 12q24.1.
In 2005, Ogata and Yoshida documented that PTPN11 mutations can be identified in approximately 40% of Noonan syndrome patients and in greater than 80% of LEOPARD syndrome patients. Because the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities.
In 2006, Hanna et al found that Noonan syndrome mutations enhance SHP-2 catalytic activity, whereas the activity of representative LS mutants is undetectable when assayed using a standard PTP substrate. The results are also supported by studies by Kontaridis et al. They revealed that whereas Noonan syndrome is caused by gain-of-function PTPN11 mutations, LEOPARD syndrome mutants are catalytically defective and act as dominant negative mutations that interfere with growth factor/Erk-mitogen-activated protein kinase–mediated signaling.
In 2006, Tartaglia et alreported that germline mutations in the PTPN11 gene cause LEOPARD and Noonan syndromes, whereas somatic mutations in the same gene contribute to leukemogenesis. To date, one patient with LEOPARD syndrome and myelomonocytic leukemia has been reported (Ucar, 2006).
Importantly, however, not all patients with LEOPARD syndrome demonstrate linkage to 12q24.1.
Reported in 2005, Kalidas et al performed mutation screening and linkage analysis of PTPN11in 3 families, each of which had a history of LEOPARD syndrome for 3 generations. One family was found to carry a novel mutation (Q510P; 176876.0022). No variations in sequence were observed in the other 2 families, and negative lod scores excluded linkage to the PTPN11locus, showing that LEOPARD syndrome is genetically heterogeneous.
Frequency
International
No epidemiologic data are available. The syndrome seems to be rare both in the United States and internationally.
Mortality/Morbidity
Most patients with LEOPARD syndrome lead a normal life. Cardiac pathologic findings (eg, obstructive cardiomyopathy, cardiac dysrhythmias) may be a cause of death in selected patients. A 19-year-old woman who died as a result of respiratory insufficiency secondary to thoracic deformities and a congenital heart defect has been reported.
Race
LEOPARD syndrome has no clear racial predilection.
Sex
In a large collected series of 77 patients, a slight preponderance of men has been documented (47 men, 30 women).
Age
Lentigines may be present at birth or develop during childhood. They become more numerous and darker with age. Other skin lesions, such as nevocellular nevi and malignant melanomas, reported sporadically in the LEOPARD syndrome, may undergo depigmentation.
History
Highly variable expressivity of the syndrome makes the diagnosis difficult, especially in sporadic patients. Seventy percent of reported cases are familial. Based on clinical analysis of a large series of patients collected from the literature, in 1976 Voron et al proposed minimum criteria for the diagnosis.
- Multiple lentigines must be present.
- Features of at least 2 other categories must be present.
- Other cutaneous abnormalities
- Cardiac structural or electrocardiographic abnormalities
- Genitourinary abnormalities
- Endocrine abnormalities
- Neurologic defects
- Cephalofacial dysmorphism
- Shortness of stature
- Skeletal abnormalities
- If lentigines are absent, a diagnosis of LEOPARD syndrome may be established if the patient has features in at least 3 above-mentioned categories and has an immediate relative with the defined diagnosis.
- Diagnosis of LEOPARD syndrome is very difficult in small children. According to Digilio et al (2006), the diagnosis can be clinically suspected in the first months of life in patients who have 3 main features: characteristic facial features (100%), hypertrophic cardiomyopathy (87%), and caféau lait spots (75%).
Physical
- Lentigines are small, dark brown, polygonal, irregularly shaped macules, usually 2-5 mm in diameter, but sometimes larger, even up to 1-1.5 cm.
- They are often present on the face, neck, and upper part of the trunk but also on the palms, soles, and the sclerae.
- Lentigines are the most prominent manifestation of the LEOPARD syndrome and are present in more than 90% of the patients; however, an absence of the feature does not exclude the diagnosis of the syndrome. Speculation about generalized lentiginosis always being a part of the spectrum of LEOPARD syndrome have been recently weakened by a study from Xing and al, who mapped familial generalized lentiginosis without systemic involvement to band 4q21.1-q22.3.
- On careful skin examination, other cutaneous abnormalities may be detected.
- Axillary freckling
- Café au lait spots
- Localized hypopigmentation
- Onychodystrophy
- Interdigital webs
- Hyperelastic skin
- Mental retardation, usually of mild degree, is observed in about 30% of the affected persons.
- About 25% of patients have sensorineural hearing loss.
- Seizures, nystagmus, or hyposmia have been documented in a few patients.
- One third of the patients demonstrate short stature (in 20% of the cases below third percentile), which seems to become evident soon after birth (most newborns are of normal birth weight).
- Despite frequent cardiac involvement, most patients are asymptomatic, and findings on routine physical examinations may be negative.
- In 2004, Yagubyan et al reported a patient with recurrent upper extremity aneurysms that required multiple operations. This patient also had multiple other peripheral aneurysms, thus far asymptomatic.
- About 35% of the patients demonstrate various cephalofacial findings. Ocular hypertelorism was the most frequently reported (25%). Other findings include the following:
- Mandibular prognathism
- Broad nasal root
- Dysmorphic skull
- Low-set ears
- Dental abnormalities
- High palate arch
- Epicanthal folds
- Ptosis
- Corneal tumors
- Developmental anomalies of the genitourinary system are described in 26% of patients, predominantly in men. Abnormalities of the external genitals, such as cryptorchidism or hypospadias, may be observed on physical examination.
- Different types of skeletal anomalies have been documented in affected patients, including chest deformity (pectus excavatum, pectus carinatum), kyphoscoliosis, winging of the scapulae, rib anomalies, syndactyly, delayed development or agenesis of permanent teeth, or supernumerary teeth.
- In 2004, Rudolph et al reported colobomas of the iris, the retina, and the choroid in 3 members of one family.
Causes
Familial cases suggest an autosomal dominant mode of inheritance with variable expressivity. Speculation exists on the more severe course of the disease in males, which may partially explain the slight preponderance of men in the large collected series of Voron et al in 1976.
Albright Syndrome
Carney Syndrome
Ephelides (Freckles)
Lentigo
Neurofibromatosis
Other Problems to be Considered
Noonan syndrome
Peutz-Jeghers syndrome
Nevi-atrial myxoma-myxoid neurofibromata-ephelides (NAME or LAMB) syndrome
Centrofacial lentiginosis
Lab Studies
- In some patients with endocrine abnormalities, low levels of follicle-stimulating hormone, luteinizing hormone, and thyrotropin and elevated levels of 17-hydroxy and 17-ketosteroids have been revealed.
Imaging Studies
- CT scanning or MRI of the head may reveal brain atrophy.
- Skeletal radiography is indicated for detection of skeletal malformations or for bone age assessment.
- Echocardiography should be done for visualization of structural heart abnormalities (eg, pulmonary valve stenosis, obstructive cardiomyopathy, myxomas).
- Assessment of the genitourinary system may require abdominal ultrasonography or urographic examination.
Other Tests
- Perform electrocardiography to exclude conduction abnormalities, which are reported in about one third of the patients. The most common electrocardiographic changes are left axis deviation, prolonged PR intervals, and right bundle branch block. Due to possible arrhythmia, ECG is especially mandatory before all planned surgical interventions.
- Due to possible arrhythmia, ECG is mandatory before all planned surgical interventions.
- EEG is recommended for patients with seizures.
- Sensorineural deafness may be detected by audiography or auditory evoked potentials.
Histologic Findings
Biopsy of a lentigo reveals an increased number of melanocytes per unit skin area and prominent rete ridges. Electron microscopic examination reveals large accumulations of melanosomes within the Langerhans cells and giant melanosomes. The latter were reported both in normal and pigmented skin in patients with the LEOPARD syndrome; they are also found in patients with neurofibromatosis and nevus spilus.
Medical Care
- Cryosurgery and laser treatment may be beneficial for isolated lentigines; however, because of the large number of lentigines it may be time consuming. For some patients, treatment with tretinoin cream and hydroquinone cream may be helpful.
- Therapeutic regimens include beta-adrenergic receptor or calcium channel blocking agents to reduce outflow tract obstruction and adrenergic responsiveness in patients with structural cardiac anomalies.
- Antiarrhythmic treatment may be required in cases with life-threatening ventricular ectopy.
Surgical Care
Surgical treatment may be necessary in cases with severe outflow tract obstruction or in patients with cryptorchidism, hypospadias, or severe skeletal deformity.
Consultations
- Genetic counseling should be offered to all patients with LEOPARD syndrome. Frequent presentation of forme fruste requires careful examination of all family members.
- Consult a cardiologist, endocrinologist, and orthopedist as dictated by history and physical examination findings.
Activity
Advise patients with outflow tract obstruction or significant cardiac dysrhythmias to avoid strenuous physical exercises.
The combination of tretinoin and hydroquinone can be used as a skin lightening agent.
Drug Category: Retinoids
Decrease cohesiveness of abnormal hyperproliferative keratinocytes and may reduce potential for malignant degeneration. Modulate keratinocyte differentiation. Have been shown to reduce risk of skin cancer formation in renal transplant patients. In this case, the combination with hydroquinone is good for topical use.
| Drug Name | Tretinoin (Avita, Retin-A) |
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| Description | Keratolytic agent. Acts by increasing epidermal cell mitosis and turnover while suppressing keratin synthesis. May help lighten lentigines, particularly when used in combination with hydroquinone. |
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| Adult Dose | Apply 0.1% cream qhs; hydroquinone cream may be applied afterwards |
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| Pediatric Dose | Not established |
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| Contraindications | Documented hypersensitivity |
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| Interactions | Irritation increases with coadministration of benzoyl peroxide, salicylic acid, and resorcinol; avoid topical sulfur, resorcinol, salicylic acid, other keratolytics, abrasives, astringents, spices, and lime |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
|
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| Precautions | Photosensitivity may occur; caution in eczema; do not apply to mucous membranes, mouth, and angles of nose, mouth or eyes (may cause excessive irritation); adverse effects include crusting, severe burning or redness, and swelling of skin |
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Drug Category: Depigmenting agents
Blocks melanogenesis and works well in combination with tretinoin.
| Drug Name | Hydroquinone USP 4% |
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| Description | Lightens hyperpigmented skin by inhibiting enzymatic oxidation of tyrosine and suppressing other melanocyte metabolic processes, thereby further inhibiting melanogenesis. Exposure to sun reverses effects and causes repigmentation. |
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| Adult Dose | Apply to affected areas bid (may be applied after tretinoin application) |
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| Pediatric Dose | <12 years: Not established
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity to drug or related products |
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| Interactions | Concurrent use of hydrogen peroxide inactivates hydroquinone, which is labile in the presence of oxygen. |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
|
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| Precautions | Adverse effects include erythema, stinging, irritation, sensitization, and contact dermatitis in sensitive individuals; application area should not exceed that of face, neck, hands, or arms. |
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Further Inpatient Care
- No further inpatient care is needed except as indicated for complications of associated abnormalities.
Further Outpatient Care
- All patients with the LEOPARD syndrome should undergo periodic cardiac assessment with echocardiography and electrocardiographic examination because the heart conduction impairment tends to occur gradually but progressively.
Deterrence/Prevention
- Genetic counseling and examination of other family members is indicated.
Complications
- Complications may arise due to associated abnormalities.
Prognosis
- Prognosis is determined mainly by cardiac complications.
Patient Education
- Genetic counseling is recommended.
Medical/Legal Pitfalls
- Failure to perform thorough evaluation to identify any associated anomalies
- Failure to offer family evaluation and genetic counseling because the autosomal dominant mode of inheritance implies the need for these
- Failure to use care in using modalities to remove the lentigines
- Failure to recognize the syndrome
| Media file 1:
Multiple lentigines on the face of a child with LEOPARD syndrome. |
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| Media file 2:
Lentigines on the sclerae in a child with LEOPARD syndrome. |
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| Media file 3:
Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome. |
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| Media file 4:
Onychodystrophy in a child with LEOPARD syndrome. |
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Media type: Photo
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| Media file 5:
Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome. |
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Media type: Photo
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LEOPARD Syndrome excerpt Article Last Updated: Jul 20, 2006
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