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Last updated:
January 10, 2018
Years published: 1989, 1997, 1998, 2007, 2012, 2018
NORD gratefully acknowledges Bruce D. Gelb, MD, The Gogel Family Professor of Child Health and Development, Professor of Pediatrics and Genetics & Genomic Sciences, Director, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai for assistance in the preparation of this report.
Summary
Noonan syndrome with multiple lentigines (NSML) 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 person to person.
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 affected individuals may also exhibit mild intellectual disability, speech difficulties, and/or, in some cases, additional physical abnormalities.
NSML is an autosomal dominant genetic disorder. NSML and Noonan syndrome are both caused by mutations in the PTPN11 and RAF1 genes.
The symptoms and physical characteristics associated with NSML are highly variable. However, most affected individuals tend to exhibit characteristic abnormalities of the skin, the structure and function of the heart, the head and facial (craniofacial) area, and/or the genitals.
Children with NSML may exhibit numerous black or dark brown “freckle-like” spots on the skin (multiple lentigines). However, most individuals with NSML do not exhibit lentigines during the first few years of life. 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.
Many individuals with NSML 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 NSML, 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.
The effects of such electrocardiographic conduction defects in individuals with NSML 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 NSML 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 abnormality 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 NSML, 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 people, hypertrophic cardiomyopathy and pulmonary stenosis may be associated.
Some 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.
Many individuals with NSML 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 NSML 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.
Individuals with NSML 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 NSML 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 NSML may also exhibit mild to severe hearing loss due to malfunction of the inner ears (sensorineural deafness). In some people, such hearing loss may be apparent at birth or during early childhood. However, other 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 people. Although most affected individuals have normal intelligence, others may exhibit mild intellectual disability.
NSML 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 NSML 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 NSML 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.
NSML is an extremely rare disorder that is believed to affect males and females in equal numbers.
In some children, the diagnosis of NSML 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 NSML 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 NSML 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 electrocardiography (EKG), echocardiography, cardiac MRI and/or cardiac catheterization. An EKG, which records the electrical activities of the heart muscle, 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. 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.
Sonographic and radiological techniques may be conducted to detect and/or confirm certain genital abnormalities in many individuals with NSML (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 NSML 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 NSML, 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 NSML 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.
Treatment
The treatment of NSML 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 NSML are symptomatic and supportive. In affected individuals who exhibit mild forms of cardiac 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 NSML, treatment with certain medications, surgical intervention, and/or other techniques may be necessary. The surgical procedures performed will depend upon the location and severity of the anatomical abnormalities and their associated symptoms.
Other abnormalities potentially associated with NSML 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 NSML demonstrate hearing impairment, hearing aids may be beneficial. 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 NSML 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 NSML 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 NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
(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.].)
TEXTBOOKS
Foad MS, Elgart ML. LEOPARD Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia, PA: Lippincott, Williams and Wilkins; 2003:124-5.
JOURNAL ARTICLES
Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. 2007;39:75-79.
Limongelli G, Pacileo G, Marino B, et al. Prevalence and clinical significance of cardiovascular abnormalities in patients with the LEOPARD syndrome. Am J Cardiol. 2007;100:736-741.
Digilio MC, Sarkozy A, de Zorzi A, et al. LEOPARD syndrome: clinical diagnosis in the first year of life. Am J Med Genet A. 2006;140(7):740-6.
Kalidas K, Shaw AC, Crosby AH, et al. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J Hum Genet. 2005;50(1):21-5.
Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev 2005; 2(4): 669-74.
Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet. 2005;6:45-68.
Chong WS, Klanwarin W, Giam YC. Generalized lentiginosis in two children lacking systemic associations: case report and review of the literature. Pediatr Dermatol. 2004;21(2):139-45.
Digilio MC, Pacileo G, Sarkozy A, et al. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. 2004;70(2):95-8.
Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with LEOPARD syndrome: A French multicentric experience. J Med Genet. 2004;41(11):e117.
Pacheco TR, Oreskovich N, Fain P: Genetic heterogeneity in the multiple lentigines/LEOPARD/Noonan syndromes. Am J Med Genet A. 2004;127(3):324-6.
Sarkozy A, Conti E, Digilio MC, et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004;41(5):e68.
Conti E, Dottorini T, Sarkozy A, et al. A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat. 2003;21(6):654.
Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. 2002;71(2):389-94.
INTERNET
Schwartz RA and Jozwiak S. LEOPARD Syndrome. Medscape. https://emedicine.medscape.com/article/1096445-overview. Updated: Jul 17, 2017. Accessed Dec. 7, 2017.
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. LEOPARD Syndrome 1. Entry No: 151100. Last Edited: 11/14/2014. Available at: https://omim.org/entry/151100 Accessed Dec. 7, 2017.
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