| Phenotype and clinics | The main clinical features of LEOPARD syndrome are multiple lentigines, congenital heart defect or electrocardiographic abnormalities, deafness, facial anomalies, urogenital malformations, skeletal anomalies, retardation of growth, and learning difficulties.
Diffuse lentiginosis is a characteristic of LEOPARD syndrome. Lentigines are brown macules, usually 2 to 8 mm in diameter, generally most heavily concentrated on the upper part of the trunk and neck, although they can also be present on the face, limbs, palms, soles and genitalia. The mucosae are characteristically spared. Lentigines are rarely present at birth and, classically, develop during childhood, increasing in number until puberty and darkening with age. Cafe-au lait patches as well as axillary freckling have also been described.
Structural cardiac defects can be detected in 70% of the patients. Hypertrophic cardiomyopathy is the most common defect. It is progressive and commonly involves the intraventricular septum. Pulmonary valve stenosis with valve leaflet dysplasia, partial atrioventricular canal and mitral valve anomalies can also be present. Arrhythmias include heart block, bundle branch block, and hemiblock.
Deafness is generally sensorineural, may be unilateral, but can be profound. Most cases have deafness diagnosed in childhood, but some are reported to have developed it in adult life.
Facial anomalies include hypertelorism, palpebral ptosis, and large low-set ears. They occur in 90% of the patients.
A high prevalence of genitourinary abnormalities has been reported especially in male patients. These include cryptorchidism, hypospadias, as well as malformations of the kidneys and collecting systems.
Pectus carinatum or excavatum are detectable. In old age, there is a tendency to develop thoracic kyphosis.
Growth retardation is frequent. The adult height is generally below the 25th centile.
Mild mental retardation and learning difficulties, so as language defects related to deafness, can occur in patients with LEOPARD syndrome.
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| Neoplastic risk | A distinct class of somatic mutations of PTPN11, appearing to have high gain-of-function levels, contributes to leukemogenesis. The identification of these mutations at a germinal level explains the higher prevalence of myeloproliferative disorders and acute leukemia among children with Noonan or LEOPARD syndrome. The RAS/MAPK pathway is deregulated in juvenile myelomonocytic leukemia due to mutations in NRAS, KRAS2 or NF1. It has be hypothesized that germline or somatic mutations in PTPN11 could also interfere with RAS/MAPK pathway.
Multiple granular cell myoblastomas, a tumor believed to arise from Schwann cells, have been reported in one patient.
Central giant cell granulomas presenting as cyst-like lesions in the mandible have also been described in LEOPARD syndrome.
Choristoma, a congenital corneal tumor containing cellular elements of ectodermal derivatives, may occasionally coexist with LEOPARD syndrome. |
| Treatment | beta-blockade or calcium channel blockers are most frequently used in treatment of obstructive cardiomyopathy. If there is no response to drug therapy, surgery for left ventricular outflow obstruction or transplantation can be indicated.
The use of lasers has been shown to be effective in the treatment of lentigines. Noninvasive agents such as tretinoin cream and hydroquinone cream used in combination have been shown to lighten lentigines after several months of application.
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| Prognosis | The prognosis is mainly determined by the nature and severity of cardiac lesions. In fact, the major concern is that of hypertrophic cardiomyopathy, because of its association with arrhythmia and sudden death. |
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