NORD gratefully acknowledges M.Cristina Digilio, MD, Medical Genetics, Bambino Gesu Hospital, Rome, Italy, for assistance in the preparation of this report.
LEOPARD syndrome is a rare genetic disorder characterized by abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. In individuals with the disorder, the range and severity of symptoms and physical characteristics may vary from case to case.
LEOPARD is an acronym for the characteristic abnormalities associated with the disorder: L stands for (L)entigines (multiple black or dark brown spots on the skin); (E)lectrocardiographic conduction defects (abnormalities of the electrical activity and the coordination of proper contractions of the heart); (0)cular hypertelorism (widely-spaced eyes); (P)ulmonary stenosis (obstruction of the normal outflow of blood from the right ventricle of the heart); (A)bnormalities of the genitals; (R)etarded growth resulting in short stature; and (D)eafness or hearing loss due to malfunction of the inner ear (sensorineural deafness). Some individuals with LEOPARD syndrome may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities. LEOPARD syndrome is an autosomal dominant genetic disorder.
LEOPARD syndrome and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes.
The symptoms and physical characteristics associated with LEOPARD syndrome are highly variable. However, most affected individuals tend to exhibit characteristic abnormalities of the skin, the structure and function of the heart, the inner ear, the head and facial (craniofacial) area, and/or the genitals. “LEOPARD,” an acronym for such characteristic abnormalities, stands for (L)entigines; (E)lectrocardiographic conduction defects; (O)cular hypertelorism; (P)ulmonary stenosis; (A)bnormalities of the genitals; (R)etarded growth; and (D)eafness (sensorineural hearing impairment).
Children with LEOPARD syndrome may exhibit numerous black or dark brown “freckle-like” spots on the skin (multiple lentigines). Lentigines increase in number with age, usually until puberty. Many affected individuals may exhibit thousands of such lentigines. Although these small, flat discolorations (macules) resemble freckles, they tend to be darker, range from approximately one to five millimeters (mm) in size, and do not darken upon exposure to sunlight. The lentigines tend to be most numerous on the neck and upper chest area (trunk), be less concentrated below the knees, and involve only the skin, not the mucous membranes. However, they may appear anywhere on the skin of the body including the scalp, face, upper arms and/or upper legs, palms of the hands, soles of the feet, and/or genitals. In approximately 20 percent of affected individuals, larger, dark brown discolorations (café-au-lait spots) may also appear on the skin. In the first years of life, individuals with LEOPARD syndrome may exhibit no lentigines.
Many individuals with LEOPARD syndrome also have cardiac anomalies. Such heart defects, which are often apparent during infancy or early childhood, may include the abnormal transmission of electrical impulses that coordinate contractions of the heart (electrocardiographic conduction defects). In many cases of LEOPARD syndrome, there may be an interruption of the normal passage of electrical impulses (heart block) through the heart’s conducting system. As a result, although the two upper chambers of the heart (atria) may beat normally, the two lower chambers (ventricles) may contract less often or “fall behind” the atria.
Individuals with LEOPARD syndrome may exhibit varying grades of heart block. In the least serious form, there may be a slight delay between the contractions of the atria and of the ventricles (termed “prolonged P-R interval,” based upon the appearance of such a delay during a specialized imaging test [electrocardiogram]). Other degrees of heart block may also occur in some cases (e.g., left anterior hemiblock, widening of the QRS complex [portion of electrocardiogram comprised of the Q, R, and S waves], and complete heart block). For example, in some cases, the delay between atrial and ventricular contractions may continue to lengthen, until a ventricular beat may be dropped altogether. In other, more severe cases of heart block, only a percentage (e.g., half, quarter, etc.) of atrial beats may be conducted to the ventricles. When complete heart block occurs, the ventricles and the atria are beating completely independently of one another.
The effects of such electrocardiographic conduction defects in individuals with LEOPARD syndrome may be highly variable, ranging from no apparent symptoms (asymptomatic) in some affected individuals to potentially serious complications in others. For example, those who exhibit prolonged P-R intervals may not exhibit any associated symptoms. Observable symptoms may also not occur in affected individuals who experience dropped beats. In more severe cases of heart block, however, if there is inadequate blood output from the ventricles, affected individuals may experience breathlessness due to the heart’s inability to pump blood effectively (heart failure), fatigue, or experience fainting episodes. If the ventricular beat slows dramatically or stops, affected individuals may black out, experience seizures, or exhibit life-threatening symptoms.
In addition, individuals with LEOPARD syndrome may also have structural (anatomical) malformations of the heart. The most common cardiac malformation appears to be overgrowth (hypertrophy) of the cardiac muscle in the ventricular wall(s) (hypertrophic obstructive cardiomyopathy), particularly the left ventricle. This condition may cause reduced cardiac output, potentially resulting in fatigue; fainting episodes (syncope), particularly during physical activity; and/or, in some cases, potentially life-threatening symptoms (e.g., arrhythmias, etc.)
The second most common defect is the obstruction of the normal outflow of blood from the lower right chamber (ventricle) of the heart to the lungs (isolated valvar pulmonary stenosis). Such obstruction may be due to abnormal narrowing (stenosis) of the pulmonary artery, which carries blood from the right ventricle to the lungs; stenosis of the pulmonary valve, the valve that controls the regular flow of deoxygenated blood through the pulmonary artery and on to the lungs; abnormal narrowing of the upper portion of the right ventricle; and/or other causes. In individuals with pulmonary stenosis, the heart must work harder to send blood to the lungs for oxygenation.
In most individuals with LEOPARD syndrome, pulmonary stenosis tends to be mild and symptoms may not occur (asymptomatic). In those cases when symptoms do occur, they often may not appear until later in childhood.
In some cases, hypertrophic cardiomyopathy and pulmonary stenosis may be associated.
In some cases, affected individuals with pulmonary stenosis may also exhibit abnormal narrowing (stenosis) of the aorta, the main artery of the body. Aortic stenosis may result in obstruction of blood flow from the left ventricle to the aorta and abnormal thickening of cardiac muscle in the wall of the left ventricle. As a result, aortic stenosis may contribute to such symptoms as fatigue, chest pain (angina pectoris) during exertion, breathlessness, and/or fainting episodes.
In addition, in many cases, individuals with LEOPARD syndrome often exhibit widely spaced eyes (ocular hypertelorism), with or without additional malformations of the head and facial (craniofacial) area. These may include a triangular-shaped face, drooping of the upper eyelids (ptosis), the presence of abnormal folds of skin over the inner corners of the eye (epicanthal folds), abnormal protrusion of the lower jaw (mandibular prognathism), and/or low-set, unusually prominent ears. Some affected individuals may also exhibit additional abnormalities including crossing of the eyes (strabismus) and/or mild webbing of the neck (pterygium colli).
Many individuals with LEOPARD syndrome may also have genital abnormalities. Affected males may exhibit abnormal placement of the urinary opening (meatus) on the underside of the penis (hypospadias), unusual smallness of the penis (micropenis), and/or failure of one or both testes to descend into the scrotum (unilateral or bilateral cryptorchidism). Affected females may exhibit underdevelopment (hypoplasia) or absence (agenesis) of an ovary. Abnormally decreased function of the gonads (i.e., testes in males, ovaries in females) may result in delayed development of secondary sexual characteristics (puberty) in some affected males and females.
In many cases, individuals with LEOPARD syndrome may also exhibit growth retardation that results in short stature. Affected individuals may also have additional skeletal abnormalities. These may include malformations of the chest (thoracic deformity) such as abnormal depression of the bone forming the center of the chest (sternum), known as “funnel chest” or pectus excavatum, or abnormal protrusion of the sternum, known as “keeled chest” or pectus carinatum. Some individuals with LEOPARD syndrome may exhibit additional skeletal abnormalities such as unusually prominent shoulder blades (winged scapula), abnormal sideways curvature of the spine (scoliosis), and/or the development of abnormal front-to-back spinal curvature (kyphosis) during later life.
Some individuals with LEOPARD syndrome may also exhibit mild to severe hearing loss due to malfunction of the inner ears (sensorineural deafness). In some cases, such hearing loss may be apparent at birth or during early childhood. However, in other cases, affected individuals may have normal hearing in early childhood yet eventually exhibit hearing loss at a later age. Hearing impairment may contribute to speech difficulties in many cases. Although most affected individuals have normal intelligence, others may exhibit mild mental retardation.
LEOPARD syndrome is an autosomal dominant genetic disorder caused by an abnormality (change) in one of two genes: PTPN11 or RAF1. Mutations in these genes also cause a different genetic condition called Noonan syndrome. Approximately 90% of individuals with LEOPARD syndrome have a mutation in the PTPN11 gene and most individuals who do not have a PTPN11 gene mutation have a RAF1 gene mutation. A single patient with a mutation in the BRAF gene, belonging to the same molecular pathway as PTPN11 and RAF1, has been described.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. It is not known how often LEOPARD syndrome is caused by a new mutation. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.
LEOPARD syndrome is an extremely rare disorder that is believed to affect males and females in equal numbers
In some cases, the diagnosis of LEOPARD Syndrome may be suspected soon after birth due to the presence of pale tan or light brown discolorations on the skin (café-au-lait spots), characteristic facial features and hypertrophic cardiomyopathy. Multiple lentigines are usually not apparent before the age of five years. When they are seen in combination with two other related features in the LEOPARD acronym or when an individual has three related features plus a parent or sibling with multiple lentigines, the diagnosis of LEOPARD syndrome can be made.
Molecular genetic testing for the PTPN11 gene and the RAF1 gene is available to confirm the diagnosis and for prenatal diagnosis.
The diagnosis of certain specific abnormalities that may occur in association with LEOPARD syndrome may be confirmed by specialized imaging studies and/or additional tests. Examination of skin samples (biopsies) under a microscope that uses light (light microscopy) or an electron beam (electron microscopy) may confirm that pigmented areas of skin represent multiple lentigines as opposed to freckles.
Children who exhibit multiple lentigines should receive prompt, thorough cardiac evaluation. If no cardiac abnormalities are revealed during such evaluation, individuals should receive periodic reassessments to detect any heart abnormalities that may develop later.
A variety of tests may be conducted to perform such a cardiac assessment. For example, the electrocardiographic conduction defects (e.g., varying degrees of heart block) and/or structural (anatomical) malformations of the heart (e.g., pulmonary and/or aortic stenosis, hypertrophic obstructive cardiomyopathy) may be confirmed by a thorough clinical examination and several specialized tests that allow physicians to evaluate the structure and function of the heart.
Clinical examination may include a physician's evaluation of heart and lung sounds through use of a stethoscope. For example, in mild asymptomatic cases of pulmonary stenosis, the condition may initially be suspected through the detection of an abnormal heart murmur during such stethoscopic evaluation. Heart block may initially be identified by detection of a slow, regular heartbeat that fails to increase during exercise.
Specialized cardiac tests may include x-ray studies, electrocardiography (EKG), vectorcardiography, echocardiography, and/or cardiac catheterization. For example, x-ray studies may reveal abnormal enlargement of the heart (cardiomegaly). An EKG, which records the electrical activities of the heart muscle, and a vectorcardiogram, which records the magnitude and direction of the heart's electrical impulses, may confirm the presence of abnormal electrical patterns such as those associated with varying degrees of heart block (e.g., prolonged P-R interval, left anterior hemiblock, widening of the QRS complex, complete heart block). During an echocardiogram, sound waves are directed toward the heart, enabling physicians to study cardiac function and motion. Echocardiography may play an essential role in helping to confirm hypertrophic obstructive cardiomyopathy.
When cardiac catheterization is performed, a small hollow tube (catheter) is inserted into a large vein and threaded through the blood vessels leading to the heart. This procedure allows physicians to determine the rate of blood flow through the heart, measure the pressure within the heart, and/or thoroughly identify anatomical abnormalities. EKG, echocardiograms, cardiac catheterization, and/or other tests may help to clarify the underlying anatomical cause and/or severity of narrowing associated with pulmonary stenosis.
Physicians may also closely evaluate the respiratory (ventilatory) capabilities of affected individuals with pulmonary stenosis and/or other heart abnormalities since associated cardiac defects may result in inadequate blood supply to the lungs and breathlessness.
Echographic and radiological techniques may be conducted to detect and/or confirm certain genital abnormalities in many individuals with LEOPARD syndrome (e.g., unilateral or bilateral cryptorchidism in affected males, hypoplastic ovaries in affected females). In addition, because deficiencies of certain hormones (gonadotrophin) may contribute to abnormally decreased function of the gonads (hypogonadism) and delayed puberty in some affected males and females, individuals with LEOPARD syndrome may be monitored closely to promptly detect such delays and laboratory tests may be conducted to screen for deficient levels of certain gonadotrophins in the blood.
In many individuals with LEOPARD syndrome, x-ray studies may also be used to confirm the presence of certain skeletal abnormalities suspected during clinical observation. Growth retardation may not become obvious until early childhood, when there may be an observable decline in the normal growth rate.
Thorough, regular hearing (audiological) evaluation should also be conducted in individuals with LEOPARD syndrome to promptly detect potential hearing impairment and help ensure early implementation of appropriate supportive measures. If hearing impairment is detected, a scanning procedure, such as computerized tomography or CT scan, may be performed to confirm the underlying cause (e.g., inner ear malformation) and characterize the type of hearing loss (e.g., sensorineural hearing impairment). During a CT scan, a computer and x-rays are used to create a film showing cross-sectional images of the structures of the inner ear.
The treatment of LEOPARD syndrome is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat disorders of the skin (dermatologists), cardiologists, specialists who diagnose and treat skeletal disorders (orthopedists), physicians who specialize in diagnosing and treating disorders of the glands (endocrinologists), specialists who assess and treat hearing problems (audiologists), speech pathologists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Specific therapies for LEOPARD syndrome are symptomatic and supportive. In affected individuals who exhibit mild forms of conduction abnormalities, treatment may not be required. However, in more severe cases when associated symptoms occur (e.g., fainting episodes) and in some cases of pulmonary stenosis, hypertrophic obstructive cardiomyopathy, and/or other structural heart abnormalities potentially associated with LEOPARD syndrome, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. In such cases, the surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms.
In some cases, other abnormalities potentially associated with LEOPARD syndrome may also be corrected surgically. These may include certain craniofacial, skeletal, genital, and/or other malformations. For example, in some affected males with cryptorchidism, hormone treatment may be administered; however, if this treatment is not successful, surgery may be performed to move the undescended testes into the scrotum and attach them in a fixed position to prevent retraction (orchiopexy).
In addition, if laboratory and additional tests demonstrate that deficient levels of gonadotrophin (hypogonadotropism) have contributed to abnormally decreased gonadal function (hypogonadism) and delayed puberty in affected males or females, sex hormone replacement therapy may be considered in some cases.
If individuals with LEOPARD syndrome demonstrate hearing impairment, hearing aids may be beneficial in some cases. Appropriate use of hearing aids, other supportive techniques, and speech therapy may help to prevent, improve, and/or correct some speech problems that may result from such hearing impairment.
Early intervention is important to ensure that children with LEOPARD syndrome reach their potential. Special services that may be beneficial to affected children include special remedial education, special social support, physical therapy, and/or other medical, social, and/or vocational services.
Genetic counseling is recommended for individuals with LEOPARD syndrome and their families.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
Contact for additional information about LEOPARD syndrome:
M.Cristina Digilio, MD
Bambino Gesù Hospital
Piazza S. Onofrio 4
00165 Roma – Italy
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, cardiac abnormalities, hearing loss, etc.].)
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