Alternative titles; symbols
SNOMEDCT: 111306001; ORPHA: 500; DO: 0080548;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.13 | LEOPARD syndrome 1 | 151100 | Autosomal dominant | 3 | PTPN11 | 176876 |
A number sign (#) is used with this entry because LEOPARD syndrome-1 (LPRD1) is caused by heterozygous mutation in the PTPN11 gene (176876) on chromosome 12q24.
Mutation in the PTPN11 gene also causes Noonan syndrome-1 (NS1; 163950), a disorder with features overlapping those of LEOPARD syndrome.
LEOPARD is an acronym for the manifestations of this syndrome as listed by Gorlin et al. (1969): multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness.
Genetic Heterogeneity of LEOPARD Syndrome
LEOPARD syndrome is a genetically heterogeneous disorder. See also LEOPARD syndrome-2 (LPRD2; 611554), caused by mutation in the RAF1 gene (164760), and LEOPARD syndrome-3 (LPRD3; 613707), caused by mutation in the BRAF gene (164757).
Walther et al. (1966) found asymptomatic cardiac changes associated with generalized lentigo in a mother and her son and daughter. The electrocardiogram in the son suggested myocardial infarction. The mother was shown by cardiac catheterization to have mild pulmonary stenosis. Similar generalized lentigines were described by Moynahan (1962) in 3 unrelated patients (2 females, 1 male). Growth was stunted. In 1 girl, one ovary was absent and the other hypoplastic. The boy had hypospadias and undescended testes. Endocardial and myocardial fibroelastosis may have been present. Intelligence was normal but behavior childish. Matthews (1968) reported mother and 2 half-sib children with generalized lentigines, electrocardiographic changes and murmurs. A history of male-to-male transmission was recorded. Lentigines were also present in the cardiac syndrome reported by Forney et al. (see mitral regurgitation, conductive deafness, etc.; 157800).
Polani and Moynahan (1972) gave a full report of 8 patients and their families. They were impressed with the occurrence of left-sided obstructive cardiomyopathy and none of their patients was deaf. They proposed the designation 'progressive cardiomyopathic lentiginosis' for this disorder. St. John Sutton et al. (1981) reported 11 patients, 10 of them male, with classic hypertrophic obstructive cardiomyopathy and lentiginosis. All were sporadic. Mental retardation, deafness, and gonadal and somatic infantilism were uncommon in this series. The 21-year-old patient of Senn et al. (1984) had severe hypertrophic obstructive cardiomyopathy for which surgery was performed on the left ventricle to relieve severe obstruction. Both parents were unaffected; both were 40 years old at the birth of the patient. Peter and Kemp (1990) described a 19-year-old woman who died as a result of respiratory insufficiency secondary to thoracic deformities which, together with a congenital heart defect, led to pulmonary hypertension. The syndrome of cafe-au-lait spots and pulmonic stenosis, described by Watson (1967), is distinct (193520).
Coppin and Temple (1997) provided a review of the condition and added 5 cases, including relatives of one of the cases described by Polani and Moynahan (1972). Coppin and Temple (1997) pointed out the difficulty of differentiating LEOPARD syndrome from Noonan syndrome (163950) given previous reports of lentiginosis without lentigines.
Shamsadini et al. (1999) described an 18-year-old Iranian girl with LEOPARD syndrome. Clinical manifestations included lentigines, ocular hypertelorism, mental and growth retardation, deaf mutism, and several patches of hair loss on her scalp. There was no family history of lentiginosis or any other inherited condition.
Schrader et al. (2009) reported a patient with LEOPARD syndrome, confirmed by genetic analysis (176876.0006), who developed multiple granular cell tumors of the skin and subcutaneous tissues during adolescence. Studies of tumor tissue did not reveal loss of heterozygosity at the PTPN11 or NF1 (613113) genes. A review of the literature on multiple granular cell tumors associated with other syndromic features indicated that many reported cases also exhibited features of neuro-cardio-facial-cutaneous syndromes, such as lentiginosis, cryptorchidism, pulmonary stenosis, ptosis, and short stature.
Lehmann et al. (2009) reported a 37-year-old woman with genetically confirmed LEOPARD syndrome who had hypertrophic cardiomyopathy, multiple lentigines, deafness, growth retardation, hypertelorism, and strabismus. Extensive cardiac workup showed biventricular apical hypertrophy, right ventricular fibrosis, and coronary artery dilatation. Pulmonary stenosis was not a feature.
Alfurayh et al. (2020) described 3 patients from 2 generations of a Saudi family with LEOPARD syndrome. The 37-year-old father had lentigines over his entire body, predominantly on his face. The initial onset of the lentigines was unknown but the number of lentigines had progressively increased until puberty. Other features included hypertelorism, joint hypermobility, and pectus excavatum. He had a history of atrial septal defect, delayed motor development, and right cryptorchidism. His 4-year-old son, who was first noted to have multiple lentigenes at 6 months of age, had a history of cryptorchidism, pectus excavatum, hypertelorism, and gross motor and speech delay. His 18-month-old son, who was noted to have a few lentigines at 2 months of age, had a history of a small atrial septal defect, a small posterior ventricular septal defect, and motor delay. Growth parameters were normal in all 3 patients.
Digilio et al. (2006) confirmed the diagnosis of LEOPARD syndrome by molecular analysis in 8 (80%) of 10 infants clinically suspected to have the disorder in the first year of life. One additional patient was subsequently found to have neurofibromatosis type I (NF1; 162200) following evaluation of the mother. Review of the clinical characteristics of the 8 LS patients with PTPN11 mutations demonstrated characteristic facial features in 100%, hypertrophic cardiomyopathy in 87%, and cafe-au-lait spots in 75%. Common facial features included hypertelorism (100%), malformed ears (87%), and low-set ears with overfolded helix (50%). Six (75%) patients had skeletal thorax anomalies.
Gorlin et al. (1969) presented evidence for dominant inheritance.
Digilio et al. (2002) screened for mutations in the PTPN11 gene, known to be mutated in Noonan syndrome, in 9 patients with LEOPARD syndrome (including a mother-daughter pair) and 2 children with Noonan syndrome who had multiple cafe-au-lait spots. In 10 of the 11 patients, they found 1 of 2 mutations: tyr279 to cys (Y279C; 176876.0005) or thr468 to met (T468M; 176876.0006).
In 4 of 6 Japanese patients with LEOPARD syndrome, Yoshida et al. (2004) identified 1 of 3 heterozygous missense mutations: Y279C, ala461 to thr (A461T; 176876.0020), or gly464 to ala (G464A; 176876.0021).
Kalidas et al. (2005) performed mutation screening and linkage analysis of PTPN11 in 3 families in each of which LEOPARD syndrome occurred in 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 PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.
In a Saudi father and his 2 sons with LEOPARD syndrome and variable phenotypes, Alfurayh et al. (2020) identified heterozygosity for the Y279C mutation in the PTPN11 gene (176876.0005).
Tartaglia et al. (2006) showed that the recurrent LEOPARD syndrome-causing Y279C (176876.0005) and T468M (176876.0006) amino acid substitutions engender loss of SHP2 catalytic activity, thus identifying a previously unrecognized behavior for this class of missense PTPN11 mutations.
Kontaridis et al. (2006) examined the enzymatic properties of mutations in PTPN11 causing LEOPARD syndrome and found that, in contrast to the activating mutations that cause Noonan syndrome and neoplasia, LEOPARD syndrome mutants are catalytically defective and act as dominant-negative mutations that interfere with growth factor/ERK-MAPK (see 176948)-mediated signaling. Molecular modeling and biochemical studies suggested that LEOPARD syndrome mutations control the SHP2 catalytic domain and result in open, inactive forms of SHP2. Kontaridis et al. (2006) concluded that the pathogenesis of LEOPARD syndrome is distinct from that of Noonan syndrome and suggested that these disorders should be distinguished by mutation analysis rather than clinical presentation.
Carvajal-Vergara et al. (2010) generated induced pluripotent stem cells (iPSCs) derived from 2 unrelated LEOPARD patients who were heterozygous for the T468M mutation in PTPN11 (176876.0006). The iPSCs were extensively characterized and produced multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. Carvajal-Vergara et al. (2010) showed that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization, and have preferential localization of NFATC4 (602699) in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wildtype iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. Carvajal-Vergara et al. (2010) also provided molecular insights into signaling pathways that may promote the disease phenotype. Carvajal-Vergara et al. (2010) showed that basic fibroblast growth factor treatment increased the phosphorylation of ERK1/2 levels over time in several cell lines but did not have a similar effect in the LEOPARD syndrome iPSCs despite higher basal phosphorylated ERK levels in the LEOPARD syndrome iPSCs compared with the other cell lines.
Limongelli et al. (2008) studied 24 LEOPARD syndrome patients, 16 with mutations in the PTPN11 gene, 2 with mutations in the RAF1 gene, and 6 in whom no mutation had been found. Patients without PTPN11 mutations showed a significantly higher frequency of family history of sudden death, increased left atrial dimensions, and cardiac arrhythmias, and seemed to be at higher risk for adverse cardiac events. Three patients with mutations in exon 13 of the PTPN11 gene had a severe form of biventricular obstructive LVH with early onset of heart failure symptoms, consistent with previous observations.
In a family in which the mother and 2 daughters had multiple lentigines syndrome, Ahlbom et al. (1995) demonstrated that the locus was not linked to the neurofibromatosis type 1 locus (NF1; 613113). Wu et al. (1996) described a de novo missense mutation (M1035R) in exon 18 of the NF1 gene in a 32-year-old woman with a prior mistaken diagnosis of LEOPARD syndrome.
Ahlbom, B. E., Dahl, N., Zetterqvist, P., Anneren, G. Noonan syndrome with cafe-au-lait spots and multiple lentigines syndrome are not linked to the neurofibromatosis type 1 locus. Clin. Genet. 48: 85-89, 1995. [PubMed: 7586657] [Full Text: https://doi.org/10.1111/j.1399-0004.1995.tb04061.x]
Alfurayh, N., Alsaif, F., Alballa, N., Zeitouni, L., Ramzan, K., Imtiaz, F., Alakeel, A. LEOPARD syndrome with PTPN11 gene mutation in three family members presenting with different phenotypes. J. Pediat. Genet. 9: 246-251, 2020. [PubMed: 32765928] [Full Text: https://doi.org/10.1055/s-0039-3400226]
Bhawan, J., Purtilo, D. T., Riordan, J. A., Saxena, V. K., Edelstein, L. Giant and 'granular melanosomes' in Leopard syndrome: an ultrastructural study. J. Cutan. Path. 3: 207-216, 1976. [PubMed: 1018060] [Full Text: https://doi.org/10.1111/j.1600-0560.1976.tb00865.x]
Capute, A. J., Rimoin, D. L., Konigsmark, B. W., Esterly, N. B., Richardson, F. Congenital deafness and multiple lentigines. A report of cases in a mother and daughter. Arch. Derm. 100: 207-213, 1969. [PubMed: 5797963]
Carvajal-Vergara, X., Sevilla, A., D'Souza, S. L., Ang, Y.-S., Schaniel, C., Lee, D.-F., Yang, L., Kaplan, A. D., Adler, E. D., Rozov, R., Ge, Y., Cohen, N., and 9 others. Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome. Nature 465: 808-812, 2010. [PubMed: 20535210] [Full Text: https://doi.org/10.1038/nature09005]
Coppin, B. D., Temple, I. K. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J. Med. Genet. 34: 582-586, 1997. [PubMed: 9222968] [Full Text: https://doi.org/10.1136/jmg.34.7.582]
Digilio, M. C., Conti, E., Sarkozy, A., Mingarelli, R., Dottorini, T., Marino, B., Pizzuti, A., Dallapiccola, B. Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am. J. Hum. Genet. 71: 389-394, 2002. [PubMed: 12058348] [Full Text: https://doi.org/10.1086/341528]
Digilio, M. C., Sarkozy, A., de Zorzi, A., Pacileo, G., Limongelli, G., Mingarelli, R., Calabro, R., Marino, B., Dallapiccola, B. LEOPARD syndrome: clinical diagnosis in the first year of life. Am. J. Med. Genet. 140A: 740-746, 2006. [PubMed: 16523510] [Full Text: https://doi.org/10.1002/ajmg.a.31156]
Gorlin, R. J., Anderson, R. C., Blaw, M. E. Multiple lentigines syndrome: complex comprising multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, sensorineural deafness, and autosomal dominant hereditary pattern. Am. J. Dis. Child. 117: 652-662, 1969. [PubMed: 5771505] [Full Text: https://doi.org/10.1001/archpedi.1969.02100030654006]
Kalidas, K., Shaw, A. C., Crosby, A. H., Newbury-Ecob, R., Greenhalgh, L., Temple, I. K., Law, C., Patel, A., Patton, M. A., Jeffery, S. Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11. J. Hum. Genet. 50: 21-25, 2005. [PubMed: 15690106] [Full Text: https://doi.org/10.1007/s10038-004-0212-x]
Kontaridis, M. I., Swanson, K. D., David, F. S., Barford, D., Neel, B. G. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J. Biol. Chem. 281: 6785-6792, 2006. [PubMed: 16377799] [Full Text: https://doi.org/10.1074/jbc.M513068200]
Lehmann, L. H., Schaeufele, T., Buss, S. J., Balanova, M., Hartschuh, W., Ehlermann, P., Katus, H. A. A patient with LEOPARD syndrome and PTPN11 mutation. Circulation 119: 1328-1329, 2009. [PubMed: 19273734] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.108.792861]
Limongelli, G., Sarkozy, A., Pacileo, G., Calabro, P., Digilio, M. C., Maddaloni, V., Gagliardi, G., Di Salvo, G., Iacomino, M., Marino, B., Dallapiccola, B., Calabro, R. Genotype-phenotype analysis and natural history of left ventricular hypertrophy in LEOPARD syndrome. Am. J. Med. Genet. 146A: 620-628, 2008. [PubMed: 18241070] [Full Text: https://doi.org/10.1002/ajmg.a.32206]
Matthews, N. L. Lentigo and electrocardiographic changes. New Eng. J. Med. 278: 780-781, 1968. [PubMed: 5638719] [Full Text: https://doi.org/10.1056/NEJM196804042781410]
Moynahan, E. J. Multiple symmetrical moles, with psychic and somatic infantilism and genital hypoplasia: first male case of a new syndrome. Proc. Roy. Soc. Med. 55: 959-960, 1962. [PubMed: 19994192]
Peter, J. R., Kemp, J. S. LEOPARD syndrome: death because of chronic respiratory insufficiency. Am. J. Med. Genet. 37: 340-341, 1990. [PubMed: 2260561] [Full Text: https://doi.org/10.1002/ajmg.1320370309]
Pickering, D., Laski, B., MacMillan, D. C., Rose, V. 'Little leopard' syndrome. Arch. Dis. Child. 46: 85-90, 1971. [PubMed: 4995347] [Full Text: https://doi.org/10.1136/adc.46.245.85]
Polani, P. E., Moynahan, E. J. Progressive cardiomyopathic lentiginosis. Quart. J. Med. 41: 205-225, 1972. [PubMed: 4672553]
Schrader, K. A., Nelson, T. N., De Luca, A., Huntsman, D. G., McGillivray, B. C. Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11. Clin. Genet. 75: 185-189, 2009. [PubMed: 19054014] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01100.x]
Selmanowitz, V. J., Orentreich, N., Felsenstein, J. M. Lentiginosis profusa syndrome (multiple lentigines syndrome). Arch. Derm. 104: 393-401, 1971. [PubMed: 5000391]
Senn, M., Hess, O. M., Krayenbuhl, H. P. Hypertrophe Kardiomyopathie und Lentiginose. Schweiz. Med. Wschr. 114: 838-841, 1984. [PubMed: 6539946]
Seuanez, H., Mane-Garzon, F., Kolski, R. Cardio-cutaneous syndrome (the 'LEOPARD' syndrome). Review of the literature and a new family. Clin. Genet. 9: 266-276, 1976. [PubMed: 1261064] [Full Text: https://doi.org/10.1111/j.1399-0004.1976.tb01574.x]
Shamsadini, S., Abazardi, H., Shamsadini, F. Leopard syndrome. (Letter) Lancet 354: 1530 only, 1999. [PubMed: 10551509] [Full Text: https://doi.org/10.1016/S0140-6736(99)03794-0]
Sommer, A., Contras, S. B., Craenen, J. M., Hosier, D. M. A family study of the leopard syndrome. Am. J. Dis. Child. 121: 520-523, 1971. [PubMed: 5581024] [Full Text: https://doi.org/10.1001/archpedi.1971.02100170102017]
St. John Sutton, M. G., Tajik, A. J., Giuliani, E. R., Gordon, H., Su, W. P. D. Hypertrophic obstructive cardiomyopathy and lentiginosis: a little known neural ectodermal syndrome. Am. J. Cardiol. 47: 214-217, 1981. [PubMed: 7193405] [Full Text: https://doi.org/10.1016/0002-9149(81)90387-8]
Swanson, S. L., Santen, R. J., Smith, D. W. Multiple lentigines syndrome: new findings of hypogonadotrophism, hyposmia, and unilateral renal agenesis. J. Pediat. 78: 1037-1039, 1971. [PubMed: 5577185] [Full Text: https://doi.org/10.1016/s0022-3476(71)80438-9]
Tartaglia, M., Martinelli, S., Stella, L., Bocchinfuso, G., Flex, E., Cordeddu, V., Zampino, G., van der Burgt, I., Palleschi, A., Petrucci, T. C., Sorcini, M., Schoch, C., Foa, R., Emanuel, P. D., Gelb, B. D. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am. J. Hum. Genet. 78: 279-290, 2006. [PubMed: 16358218] [Full Text: https://doi.org/10.1086/499925]
Voron, D. A., Hatfield, H. H., Kalkhoff, R. K. Multiple lentigines syndrome: case report and review of the literature. Am. J. Med. 60: 447-456, 1976. [PubMed: 1258892] [Full Text: https://doi.org/10.1016/0002-9343(76)90764-6]
Walther, R. J., Polansky, B., Grots, I. A. Electrocardiographic abnormalities in a family with generalized lentigo. New Eng. J. Med. 275: 1220-1225, 1966. [PubMed: 5921856] [Full Text: https://doi.org/10.1056/NEJM196612012752203]
Watson, G. H. Pulmonary stenosis, cafe-au-lait spots, and dull intelligence. Arch. Dis. Child. 42: 303-307, 1967. [PubMed: 6025371] [Full Text: https://doi.org/10.1136/adc.42.223.303]
Weiss, L. W., Zelickson, A. S. Giant melanosomes in multiple lentigines syndrome. Arch. Derm. 113: 491-494, 1977. [PubMed: 848980]
Wu, R., Legius, E., Robberecht, W., Dumoulin, M., Cassiman, J.-J., Fryns, J.-P. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum. Mutat. 8: 51-56, 1996. [PubMed: 8807336] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:1<51::AID-HUMU7>3.0.CO;2-S]
Yoshida, R., Nagai, T., Hasegawa, T., Kinoshita, E., Tanaka, T., Ogata, T. Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome. (Letter) Am. J. Med. Genet. 130A: 432-434, 2004. [PubMed: 15389709] [Full Text: https://doi.org/10.1002/ajmg.a.30281]