1/9. A novel PTPN11 mutation in leopard syndrome. 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. ( info) |
2/9. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with leopard syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. 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. ( info) |
| leopard syndrome, one of many cardiocutaneous syndromes, is an acronym for some of the obvious manifestations of the disease, such as lentigines or ocular hypertelorism. The synonymous name progressive cardiomyopathic lentiginosis better indicates the morbid cardiac features that patients with the syndrome have. A patient with leopard syndrome is presented. He had recurrent upper extremity aneurysms requiring multiple operations and finally PTFE reinforced venous grafts to prevent further aneurysmal degeneration. He has multiple other peripheral aneurysms, thus far asymptomatic. His diagnosis of leopard syndrome was confirmed on a genetic basis. review of the literature reveals no previous reports of severe aneurysmal disease in these patients. ( info) |
4/9. Anaesthetic implications of leopard syndrome. leopard syndrome is a neuroectodermal disorder presumed to result from an abnormality in neural crest cells. The acronym 'LEOPARD' is derived from the clinical features which include multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retarded growth, and deafness. Given the multisystem nature of the disease process, several issues may affect the perioperative care of these patients. Of primary importance are associated conditions of the cardiovascular system including congenital heart disease, conduction disturbances, and progressive hypertrophic obstructive cardiomyopathy. The authors present a 4-year old boy who presented for anaesthetic care for repair of a ventricular septal defect and pulmonary valvotomy for congenital pulmonary stenosis. The potential perioperative implications of leopard syndrome are discussed. ( info) |
5/9. c-kit Mutation in generalized lentigines associated with gastrointestinal stromal tumor. We describe the case of a 59-year-old Japanese woman presenting with generalized lentigines without systemic anomalies. She had a medical history of gastrointestinal stromal tumors (GISTs), in which gain-of-function mutations of the c-kit gene had recently been found. We detected a point mutation at codon 557 in exon 11 of leukocyte dna from the patient. The stem cell factor-type III receptor tyrosine kinase pathway plays important roles in the regulation of melanocyte proliferation and differentiation. We speculate that the generalized lentigines of the patient may be caused by melanocyte proliferation due to the c-kit gene mutation. ( info) |
6/9. A novel PTPN11 gene mutation bridges noonan syndrome, multiple lentigines/leopard syndrome and Noonan-like/multiple giant cell lesion syndrome. Noonan (NS) and multiple lentigines/LEOPARD syndromes (LS) have proved to be associated with distinct PTPN11 mutations. Noonan-like/multiple giant cell lesion syndrome (NLS) is a rare disease, characterised by short stature, facial dysmorphisms, congenital heart defect (CHD) and central giant cell lesions. PTPN11 gene mutations have been reported in a single NLS family and two sporadic patients. Here we report a patient with a complex phenotype progressing throughout the years from NS at birth towards LS and NLS. PTPN11 gene analysis disclosed a novel missense mutation (Ala461Thr) in exon 12, affecting the consensus sequence of the SHP2-active site. This observation joins together NS and LS to NLS into a unique genetic defect, broadening the clinical and molecular spectrum of PTPN11-related disorders. ( info) |
7/9. leopard syndrome and hypertrophic obstructive cardiomyopathy: a case report. The leopard syndrome is a rare, autosomal dominant multisystemic disorder characterized by lentiginosis, ocular hypertelorism, abnormal genitalia, growth retardation, sensorineural deafness, and cardiac and electrocardiographic abnormalities. Although it is not cited, hypertrophic cardiomyopathy is often associated with the disease. In this study, we present a nine-year-old boy with leopard syndrome and hypertrophic obstructive cardiomyopathy. ( info) |
| 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. ( info) |
9/9. Acute myelomonocytic leukemia in a boy with leopard syndrome (PTPN11 gene mutation positive). 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). ( info) |