G2Cdb::Human Disease report

Disease id
D00000304
Name
Leopard syndrome
Nervous system disease
no

Genes (1)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12058348) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (12161596) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14634749) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14961557) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (14991917) Single nucleotide polymorphism (SNP) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15389709) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15520399) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15690106) Microinsertion (MI) ?
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (15886577) Unknown (?) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16172598) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16679933) Microinsertion (MI) Y
G00001453 PTPN11
protein tyrosine phosphatase, non-receptor type 11
Y (16733669) Microinsertion (MI) Y

References

  • PTPN11 gene mutations: linking the Gln510Glu mutation to the "LEOPARD syndrome phenotype".

    Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy, digilio@opbg.net.

    We describe the "LEOPARD syndrome (LS) phenotype" associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, café-au-lait spots and multiple lentigines.

    European journal of pediatrics 2006;165;11;803-5

  • Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive).

    Uçar C, Calýskan U, Martini S and Heinritz W

    Pediatric Hematology Unit, Department of Pediatrics, Selçuk University, Meram Faculty of Medicine, Konya, Turkey. canan.ucar@deu.edu.tr

    The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).

    Journal of pediatric hematology/oncology 2006;28;3;123-5

  • [PTPN11 gene mutation in LEOPARD syndrome].

    Paradisi M, Pedicelli C, Ciasulli A, Pinto F, Conti E, Sarkozy A and Angelo C

    Sezione di Dermatologia Pediatrica, Istituto Dermopatico dell'Immacolata (IDI), Rome. m.paradisi@idi.it

    The multiple lentigines/LEOPARD syndrome (ML/LS) is a rare and complex genetic syndrome. It is an autosomal dominant disorder with a variable expressivity. The syndrome is mainly characterised by growth retardation, multiple lentigines, and congenital heart diseases with electrocardiographic anomalies, dysmorphia of the face and deafness. The incidence of this pathology is still unknown and a familial inheritance is present in 70% of cases. Some of the ML/LS clinical features are the same as those of the Noonan syndrome (NS), such as congenital cardiac abnormalities, dysmorphia and growth retardation. NS and ML/LS are caused by allele mutations of the PTPN11 gene. We report the case of a 3-year-old girl, who was observed for the presence of widespread lentigines, a 1/6-protosystolic murmur at the mesocardium and growth retardation. The diagnosis of ML/LS was made and thus a molecular analysis of the PTPN11 gene was carried out, directly sequencing the codifying region. The molecular analysis revealed a missense mutation (A836G) in hexone 7 (TYR279CYS) of the PTPNII gene. This mutation is has been observed, at present, in a few cases of ML/LS and Noonan syndrome.

    Minerva pediatrica 2005;57;4;189-93

  • [Noonan syndrome and Leopard syndrome linked to mutation of the gene PTPN11].

    Dereure O

    Service de Dermatologie, Hôpital Saint-Eloi, 80, avenue Augustin Fliche, 34295 Montpellier Cedex 5.

    Annales de dermatologie et de venereologie 2005;132;4;400

  • Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11.

    Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, Law C, Patel A, Patton MA and Jeffery S

    Medical Genetics Unit, Department of Clinical Developmental Sciences, St. George's Hospital Medical School, London, SW17 0RE, UK.

    LEOPARD syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) is an autosomal dominant condition. The main clinical features include multiple lentigines, cardiovascular defects, and facial anomalies, some of which are shared with Noonan syndrome (NS). Recent reports have shown that LEOPARD syndrome can be caused by mutations in PTPN11, the gene in which mutations can produce NS. Here we report the findings of mutation screening and linkage analysis of PTPN11 in three families with LEOPARD syndrome. We identified a novel mutation in one family. The mutation (1529A>C) substitutes proline for glutamine at amino acid 510 (Gln510Pro). No variations in sequence were observed in the other two families, and negative LOD scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.

    Journal of human genetics 2005;50;1;21-25

  • Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome.

    Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T and Ogata T

    American journal of medical genetics. Part A 2004;130A;4;432-4

  • PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience.

    Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H and French Collaborative Noonan Study Group

    Laboratoire de Biochimie Génétique, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France. cave@infobiogen.fr.

    Journal of medical genetics 2004;41;11;e117

  • Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations.

    Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, Marino B, Pizzuti A, Calabrò R and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy. digilio@opbg.net

    Background: Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM. Additional features of the syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD syndrome.

    Cases: We report here on a patient with HCM presenting with classic clinical features of LEOPARD syndrome, whose father also has HCM, but lacks phenotypic anomalies of the syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members.

    Conclusions: Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations.

    Birth defects research. Part A, Clinical and molecular teratology 2004;70;2;95-8

  • [Molecular genetic mutation analysis of the PTPN11 gene in the multiple lentigines (LEOPARD) syndrome].

    Froster UG, Glander HJ and Heinritz W

    Institut für Humangenetik, Universität Leipzig, Leipzig. reichsi@medizin.uni-leipzig.de

    LEOPARD syndrome (MIM #151100) is a rare autosomal dominant condition with characteristic skin anomalies, facial dysmorphism, hypertelorism, cardiac anomalies, and occasional conductive hearing loss. Mutations in the PTPN11 gene are described as the causal gene defect for the clinical features of Noonan syndrome (MIM #163950), but also for LEOPARD syndrome. For confirmation of the clinical diagnosis of multiple lentigines syndrome, the molecular genetic mutation analysis in the PTPN11 gene could be helpful.

    We report on a family with LEOPARD syndrome in which the mutation analysis in the father and his daughter in the PTPN11 gene was carried out us:ng PCR, DHPLC, and automated sequencing.

    Results: We could identify both father and daughter as carriers of the mutation Y279C in the PTPN11 gene, which is known as a disease-related mutation.

    Conclusions: The allelic affinity to Noonan syndrome could thus be further supported.

    Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 2003;54;12;1190-2

  • A novel PTPN11 mutation in LEOPARD syndrome.

    Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A and Dallapiccola B

    Ospedale CSS, IRCCS, San Giovanni Rotondo, Italy.

    PTPN11 gene mutations are common to both patients with Noonan (NS) and LEOPARD syndrome (LS). So far only two recurrent mutations have been identified in LS patients by different research groups, i.e., Tyr279Cys and Thr468Met. In this work we describe the third PTPN11 mutation that has been found in a single LS patient. The mutation (c.1517A>C) substitutes a proline for a glutamine at amino acid 506 (Gln506Pro) in the phosphatase domain (PTP) of the PTPN11 peptide SHP2. This region is a mutation hotspot. Changes at amino acids 501 to 504 cause NS. Gln506Pro is predicted, by modeling analysis, to seriously disrupt the normal contacts between the regulating N-SH2 and the active PTP domains, leading to hyperactivity of the phosphatase. This report demonstrates that rarer mutations other than Tyr279Cys and Thr468Met can be found in LS patients and the need of screening the whole gene in those negative for the commonest mutations.

    Human mutation 2003;21;6;654

  • Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.

    Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A and Dallapiccola B

    Division of Medical Genetics, Bambino Gesù Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

    Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and café au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple café au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.

    American journal of human genetics 2002;71;2;389-94

  • PTPN11 mutations in LEOPARD syndrome.

    Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M and Fryns JP

    Centre for Human Genetics, University Hospitals, Leuven, Belgium. Eric.Legius@med.kuleuven.ac.be

    LEOPARD syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Deafness and genital abnormalities are less frequently found. We report a father and daughter and a third, unrelated patient with LEOPARD syndrome. Recently, missense mutations in the PTPN11 gene located in 12q24 were found to cause Noonan syndrome. All three cases of LEOPARD syndrome reported here have a Y279C mutation in the PTPN11 gene. We hypothesise that some PTPN11 mutations are associated with the typical Noonan syndrome phenotype and that other mutations, such as the Y279C mutation reported here, are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or café au lait spots.

    Journal of medical genetics 2002;39;8;571-4

Literature (12)

Pubmed - human_disease

  • PTPN11 gene mutations: linking the Gln510Glu mutation to the "LEOPARD syndrome phenotype".

    Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy, digilio@opbg.net.

    We describe the "LEOPARD syndrome (LS) phenotype" associated with the Gln510Glu mutation of the PTPN11 gene in two patients presenting with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy and structural abnormalities of the mitral valve, facial anomalies, café-au-lait spots and multiple lentigines.

    European journal of pediatrics 2006;165;11;803-5

  • [PTPN11 gene mutation in LEOPARD syndrome].

    Paradisi M, Pedicelli C, Ciasulli A, Pinto F, Conti E, Sarkozy A and Angelo C

    Sezione di Dermatologia Pediatrica, Istituto Dermopatico dell'Immacolata (IDI), Rome. m.paradisi@idi.it

    The multiple lentigines/LEOPARD syndrome (ML/LS) is a rare and complex genetic syndrome. It is an autosomal dominant disorder with a variable expressivity. The syndrome is mainly characterised by growth retardation, multiple lentigines, and congenital heart diseases with electrocardiographic anomalies, dysmorphia of the face and deafness. The incidence of this pathology is still unknown and a familial inheritance is present in 70% of cases. Some of the ML/LS clinical features are the same as those of the Noonan syndrome (NS), such as congenital cardiac abnormalities, dysmorphia and growth retardation. NS and ML/LS are caused by allele mutations of the PTPN11 gene. We report the case of a 3-year-old girl, who was observed for the presence of widespread lentigines, a 1/6-protosystolic murmur at the mesocardium and growth retardation. The diagnosis of ML/LS was made and thus a molecular analysis of the PTPN11 gene was carried out, directly sequencing the codifying region. The molecular analysis revealed a missense mutation (A836G) in hexone 7 (TYR279CYS) of the PTPNII gene. This mutation is has been observed, at present, in a few cases of ML/LS and Noonan syndrome.

    Minerva pediatrica 2005;57;4;189-93

  • [Noonan syndrome and Leopard syndrome linked to mutation of the gene PTPN11].

    Dereure O

    Service de Dermatologie, Hôpital Saint-Eloi, 80, avenue Augustin Fliche, 34295 Montpellier Cedex 5.

    Annales de dermatologie et de venereologie 2005;132;4;400

  • [Molecular genetic mutation analysis of the PTPN11 gene in the multiple lentigines (LEOPARD) syndrome].

    Froster UG, Glander HJ and Heinritz W

    Institut für Humangenetik, Universität Leipzig, Leipzig. reichsi@medizin.uni-leipzig.de

    LEOPARD syndrome (MIM #151100) is a rare autosomal dominant condition with characteristic skin anomalies, facial dysmorphism, hypertelorism, cardiac anomalies, and occasional conductive hearing loss. Mutations in the PTPN11 gene are described as the causal gene defect for the clinical features of Noonan syndrome (MIM #163950), but also for LEOPARD syndrome. For confirmation of the clinical diagnosis of multiple lentigines syndrome, the molecular genetic mutation analysis in the PTPN11 gene could be helpful.

    We report on a family with LEOPARD syndrome in which the mutation analysis in the father and his daughter in the PTPN11 gene was carried out us:ng PCR, DHPLC, and automated sequencing.

    Results: We could identify both father and daughter as carriers of the mutation Y279C in the PTPN11 gene, which is known as a disease-related mutation.

    Conclusions: The allelic affinity to Noonan syndrome could thus be further supported.

    Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete 2003;54;12;1190-2

Pubmed - other

  • Acute myelomonocytic leukemia in a boy with LEOPARD syndrome (PTPN11 gene mutation positive).

    Uçar C, Calýskan U, Martini S and Heinritz W

    Pediatric Hematology Unit, Department of Pediatrics, Selçuk University, Meram Faculty of Medicine, Konya, Turkey. canan.ucar@deu.edu.tr

    The LEOPARD syndrome is a complex of multisystemic congenital abnormalities characterized by lentiginosis, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormalities of genitalia, retardation of growth, and deafness (sensorineural). Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located on chromosome 12q24.1, have been identified in 88% of patients with LEOPARD syndrome. A missense mutation (836-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in this patient and his mother with LEOPARD syndrome. This mutation is one of the two recurrent mutations most often associated with the syndrome. Leukemia has not previously been reported in patients with LEOPARD syndrome. The authors describe a 13-year-old boy diagnosed with both LEOPARD syndrome and acute myelomonocytic leukemia (AML-M4).

    Journal of pediatric hematology/oncology 2006;28;3;123-5

  • Genetic heterogeneity in LEOPARD syndrome: two families with no mutations in PTPN11.

    Kalidas K, Shaw AC, Crosby AH, Newbury-Ecob R, Greenhalgh L, Temple IK, Law C, Patel A, Patton MA and Jeffery S

    Medical Genetics Unit, Department of Clinical Developmental Sciences, St. George's Hospital Medical School, London, SW17 0RE, UK.

    LEOPARD syndrome (lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) is an autosomal dominant condition. The main clinical features include multiple lentigines, cardiovascular defects, and facial anomalies, some of which are shared with Noonan syndrome (NS). Recent reports have shown that LEOPARD syndrome can be caused by mutations in PTPN11, the gene in which mutations can produce NS. Here we report the findings of mutation screening and linkage analysis of PTPN11 in three families with LEOPARD syndrome. We identified a novel mutation in one family. The mutation (1529A>C) substitutes proline for glutamine at amino acid 510 (Gln510Pro). No variations in sequence were observed in the other two families, and negative LOD scores excluded linkage to the PTPN11 locus, showing that LEOPARD syndrome is genetically heterogeneous.

    Journal of human genetics 2005;50;1;21-25

  • Two novel and one recurrent PTPN11 mutations in LEOPARD syndrome.

    Yoshida R, Nagai T, Hasegawa T, Kinoshita E, Tanaka T and Ogata T

    American journal of medical genetics. Part A 2004;130A;4;432-4

  • PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience.

    Keren B, Hadchouel A, Saba S, Sznajer Y, Bonneau D, Leheup B, Boute O, Gaillard D, Lacombe D, Layet V, Marlin S, Mortier G, Toutain A, Beylot C, Baumann C, Verloes A, Cavé H and French Collaborative Noonan Study Group

    Laboratoire de Biochimie Génétique, Hôpital Robert Debré, 48, Boulevard Sérurier, 75019 Paris, France. cave@infobiogen.fr.

    Journal of medical genetics 2004;41;11;e117

  • Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations.

    Digilio MC, Pacileo G, Sarkozy A, Limongelli G, Conti E, Cerrato F, Marino B, Pizzuti A, Calabrò R and Dallapiccola B

    Medical Genetics, Bambino Gesù Hospital, Rome, Italy. digilio@opbg.net

    Background: Nonsyndromic hypertrophic cardiomyopathy (HCM) is a primary cardiac disease transmitted as an autosomal dominant trait. Multiple chromosomal loci have been found to be involved in the etiology of this defect. LEOPARD syndrome is a genetic condition characteristically associated with HCM. Additional features of the syndrome include multiple lentigines, facial anomalies, sensorineural deafness, and growth retardation. Mutations in PTPN11, a gene encoding the protein tyrosine phosphatase SHP-2 located at chromosome 12q24, have been identified in patients with LEOPARD syndrome.

    Cases: We report here on a patient with HCM presenting with classic clinical features of LEOPARD syndrome, whose father also has HCM, but lacks phenotypic anomalies of the syndrome. Molecular analysis searching for PTPN11 mutations was performed in this family. A missense mutation (836A-->G; Tyr279Cys) in exon 7 of PTPN11 gene was identified in the patient with LEOPARD syndrome, whereas no mutation in PTPN11 gene was detected in the father or in additional family members.

    Conclusions: Aggregation of syndromic and nonsyndromic HCM in the same family is an unusual pattern of recurrence. Although genetic heterogeneity of LEOPARD and nonsyndromic HCM is not disputed, the existence of peculiar interactions linking genes causing nonsyndromic HCM and HCM in LEOPARD syndrome can be hypothesized. Different genes can work together, and a more severe cardiac phenotype can be due to additive effects. The involvement of familial susceptibility to specific cardiac malformations based on the presence of common predisposing factors can also be considered. Further molecular studies may shed light on these observations.

    Birth defects research. Part A, Clinical and molecular teratology 2004;70;2;95-8

  • A novel PTPN11 mutation in LEOPARD syndrome.

    Conti E, Dottorini T, Sarkozy A, Tiller GE, Esposito G, Pizzuti A and Dallapiccola B

    Ospedale CSS, IRCCS, San Giovanni Rotondo, Italy.

    PTPN11 gene mutations are common to both patients with Noonan (NS) and LEOPARD syndrome (LS). So far only two recurrent mutations have been identified in LS patients by different research groups, i.e., Tyr279Cys and Thr468Met. In this work we describe the third PTPN11 mutation that has been found in a single LS patient. The mutation (c.1517A>C) substitutes a proline for a glutamine at amino acid 506 (Gln506Pro) in the phosphatase domain (PTP) of the PTPN11 peptide SHP2. This region is a mutation hotspot. Changes at amino acids 501 to 504 cause NS. Gln506Pro is predicted, by modeling analysis, to seriously disrupt the normal contacts between the regulating N-SH2 and the active PTP domains, leading to hyperactivity of the phosphatase. This report demonstrates that rarer mutations other than Tyr279Cys and Thr468Met can be found in LS patients and the need of screening the whole gene in those negative for the commonest mutations.

    Human mutation 2003;21;6;654

  • Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene.

    Digilio MC, Conti E, Sarkozy A, Mingarelli R, Dottorini T, Marino B, Pizzuti A and Dallapiccola B

    Division of Medical Genetics, Bambino Gesù Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy.

    Multiple-lentigines (ML)/LEOPARD (multiple lentigines, electrocardiographic-conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness) syndrome is an autosomal dominant condition--characterized by lentigines and café au lait spots, facial anomalies, cardiac defects--that shares several clinical features with Noonan syndrome (NS). We screened nine patients with ML/LEOPARD syndrome (including a mother-daughter pair) and two children with NS who had multiple café au lait spots, for mutations in the NS gene, PTPN11, and found, in 10 of 11 patients, one of two new missense mutations, in exon 7 or exon 12. Both mutations affect the PTPN11 phosphotyrosine phosphatase domain, which is involved in <30% of the NS PTPN11 mutations. The study demonstrates that ML/LEOPARD syndrome and NS are allelic disorders. The detected mutations suggest that distinct molecular and pathogenetic mechanisms cause the peculiar cutaneous manifestations of the ML/LEOPARD-syndrome subtype of NS.

    American journal of human genetics 2002;71;2;389-94

  • PTPN11 mutations in LEOPARD syndrome.

    Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M and Fryns JP

    Centre for Human Genetics, University Hospitals, Leuven, Belgium. Eric.Legius@med.kuleuven.ac.be

    LEOPARD syndrome is an autosomal dominant disorder with multiple lentigines, congenital cardiac abnormalities, ocular hypertelorism, and retardation of growth. Deafness and genital abnormalities are less frequently found. We report a father and daughter and a third, unrelated patient with LEOPARD syndrome. Recently, missense mutations in the PTPN11 gene located in 12q24 were found to cause Noonan syndrome. All three cases of LEOPARD syndrome reported here have a Y279C mutation in the PTPN11 gene. We hypothesise that some PTPN11 mutations are associated with the typical Noonan syndrome phenotype and that other mutations, such as the Y279C mutation reported here, are associated with both the Noonan syndrome phenotype and with skin pigmentation anomalies, such as multiple lentigines or café au lait spots.

    Journal of medical genetics 2002;39;8;571-4

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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