LEOPARD Syndrome

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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.

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

Molecular studies have proven 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.[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.[2] 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.[3] The results are also supported by studies by Kontaridis et al.[4] 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 al reported that germline mutations in the PTPN11 gene cause LEOPARD and Noonan syndromes, whereas somatic mutations in the same gene contribute to leukemogenesis.[5] To date, 2 patients with LEOPARD syndrome and myelomonocytic or acute lymphoblastic leukemias have been reported.[6, 7]

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 PTPN11 in 3 families, each of which had a history of LEOPARD syndrome for 3 generations.[8] 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 PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.

Writzl et al reported a family with molecularly proven (p.Thr468Met in PTPN11) LEOPARD syndrome in a father and his adult son.[9] The father had multiple lentigines equally dispersed over his body as depicted below, whereas his son was devoid of lentigines on the left part of the thorax, back, and left arm. In addition, the son was found to have a mosaic karyotype in lymphocytes (47, XXY/46XY). On skin biopsy, mainly 47,XXY karyotype was present in the pigmented skin and 46,XY karyotype in the unpigmented areas. The authors considered various pathogenetic mechanisms: revertant mosaicism, silencing of a second PTPN11 mutation, genes located on a sex chromosome influencing the phenotype, and epigenetic influences.


View Image

Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.

Epidemiology

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.[10]

Physical

Causes

Familial cases suggest an autosomal dominant mode of inheritance with variable expressivity.[19] 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.[10]

Laboratory Studies

Imaging Studies

Other Tests

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

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

Activity

Advise patients with outflow tract obstruction or significant cardiac dysrhythmias to avoid strenuous physical exercises.

Medication Summary

The combination of tretinoin and hydroquinone can be used as a skin lightening agent.

Tretinoin topical (Avita, Retin-A)

Clinical Context:  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.

Class Summary

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.

Hydroquinone

Clinical Context:  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.

Class Summary

Blocks melanogenesis and works well in combination with tretinoin.

Further Inpatient Care

Further Outpatient Care

Deterrence/Prevention

Complications

Prognosis

Author

Sergiusz Jozwiak, MD, PhD, Head, Professor, Department of Child Neurology, The Children's Memorial Health Institute of Warsaw, Poland

Disclosure: Novartis Honoraria Speaking and teaching

Coauthor(s)

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Disclosure: Nothing to disclose.

Specialty Editors

James J Nordlund, MD, Professor Emeritus, Department of Dermatology, University of Cincinnati College of Medicine

Disclosure: Nothing to disclose.

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA

Disclosure: Nothing to disclose.

Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas School of Medicine at San Antonio

Disclosure: Nothing to disclose.

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

Additional Contributors

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous Chief Editor, William D. James, MD, to the development and writing of this article.

References

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Multiple lentigines on the face of a child with LEOPARD syndrome.

Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.

Lentigines on the sclerae in a child with LEOPARD syndrome.

Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome.

Onychodystrophy in a child with LEOPARD syndrome.

Multiple lentigines on the face of a child with LEOPARD syndrome.

Lentigines on the sclerae in a child with LEOPARD syndrome.

Area of disordered pigmentation on the trunk of a patient with LEOPARD syndrome.

Onychodystrophy in a child with LEOPARD syndrome.

Multiple, small lentigines evenly distributed over the trunk of an adult female with LEOPARD syndrome.