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Research Letter |

A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome FREE

Aurélie Du-Thanh, MD; Hélène Cave, PharmD, PhD; Didier Bessis, MD; Carine Puso, MD; Jean-Jacques Guilhou, MD; Olivier Dereure, MD, PhD
Arch Dermatol. 2007;143(9):1209-1226. doi:10.1001/archderm.143.9.1210.
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Published online

In 1969, Gorlin et al1 described an autosomal dominant syndrome encompassing multiple lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, currently known as LEOPARD syndrome (LS). Recently, it has been reported that most cases of LS are probably related to heterozygous mutations of PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11), a gene encoding a tyrosine-phosphatase protein named SHP-2, with 2 particular “hot spots” in exons 7 and 12.25 Despite overlapping clinical manifestations, LS is distinct from Noonan syndrome, another PTPN11 gene mutation–related disorder but with a different mutation spectrum. Herein we report the first case to our knowledge of typical LS featuring a new PTPN11 gene mutation.

A 39-year-old woman with a medical history of deafness and a familial background of Down syndrome in a sister was referred for evaluation of pigmentary changes that first appeared during infancy associated with mild facial dysmorphism. Clinical examination disclosed multiple light or dark brown macules of varied sizes scattered throughout her whole body surface including her face, palmoplantar areas, lips, and conjunctiva (Figure 1). There were no lentigines on the other mucous membranes. Facial examination revealed hypertelorism. Electrocardiography showed a first-degree atrioventricular block, whereas heart ultrasound evaluation did not find any valve abnormality. Hearing investigations confirmed sensorineural deafness. There were no urogenital abnormalities, endocrinopathy, or growth retardation. A diagnosis of LS was established based on the presence of 4 criteria.

Place holder to copy figure label and caption
Figure 1.

Numerous lentiginous elements scattered throughout the trunk.

Graphic Jump Location

After obtaining the patient's consent, we undertook direct sequencing of the PTPN11 coding region and discovered a previously undescribed (to our knowledge) heterozygous missense mutation in exon 13, namely a G1493T transversion leading to an R498L change in amino acid sequence (Figure 2). No genetic analysis of her relatives could be carried out to establish a diagnosis of de novo or inherited mutation.

Place holder to copy figure label and caption
Figure 2.

Genomic structure of the PTPN11 gene and corresponding functional organization of the PTPN11-encoded SHP-2 phosphatase. Exons are represented as shaded boxes. Also shown are the main LEOPARD syndrome–associated mutations (hot spots Y279C and T468M) and our patient's R498L mutation affecting exon 13. N and C are terminal indicators; PTP indicates protein-tyrosine phosphatase; SH2, Src homology 2.

Graphic Jump Location

The SHP-2 phosphatase plays several important roles in cellular physiologic function, mainly in cell proliferation, differentiation, migration, and adhesion.68 This protein contains 2 main domains: a C-terminal protein-tyrosine phosphatase (PTP) domain involved in catalytic activity and 2 N-terminal Src homology 2 (SH2) domains interacting with the PTP domain, keeping it folded and inactive (Figure 2).3 To our knowledge, only 7 PTPN11 mutations have been reported in patients with LS, all of them in the PTP domain in exons 7 (Y279C and Y279S), 12 (T468M and A461T), and 13 (Q506P, Q510E, and Q510G).2,4,911 Two of them (Y279C and T468M) represent more than 90% of the identified changes. The mutational site in our patient is close to the PTP-SH2 domains interacting tract and to the previously reported mutations affecting exon 13. Accordingly, this change is probably relevant as to LS pathomechanisms. PTPN11 mutations in Noonan syndrome are likely to result in a gain of function with “permanent” catalytic activity of the protein, whereas recent results unexpectedly suggest that LS-related PTPN11 mutations result in a decrease in the phosphatase function of SHP-2.1214 Understanding why topographically closely related mutations on the same gene may have opposite functional consequences but still result in close phenotypes will be a rewarding challenge.

Correspondence: Dr Dereure, Department of Dermatology, University of Montpellier I, Hôpital Saint-Eloi, 80 Ave A. Fliche, 34295 Montpellier CEDEX 5, France (o-dereure@chu-montpellier.fr).

Financial Disclosure: None reported.

Gorlin  RJAnderson  RCBlaw  M Multiple lentigenes syndrome. Am J Dis Child 1969;117 (6) 652- 662
PubMed Link to Article
Digilio  MCConti  ESarkozy  A  et al.  Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71 (2) 389- 394
PubMed Link to Article
Legius  ESchrander-Stumpel  CSchollen  EPulles-Heintzberger  CGewillig  MFryns  JP PTPN11 mutations in LEOPARD syndrome. J Med Genet 2002;39 (8) 571- 574
PubMed Link to Article
Keren  BHadchouel  ASaba  S  et al.  PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet 2004;41 (11) e117
PubMed Link to Article
Ogata  TYoshida  R PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev 2005;2 (4) 669- 674
PubMed
Kroll  JWaltenberger  J The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 1997;272 (51) 32521- 32527
PubMed Link to Article
Chang  YCeacareanu  BDixit  MSreejayan  NHassid  A Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res 2002;91 (5) 390- 397
PubMed Link to Article
Maheshwari  MBelmont  JFernbach  S  et al.  PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exon 3 and 13. Hum Mutat 2002;20 (4) 298- 304
PubMed Link to Article
Conti  EDottorino  TSarkozy  A  et al.  A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat 2003;21 (6) 654
PubMed Link to Article
Sarkozy  AObregon  MGConti  E  et al.  A novelPTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet 2004;12 (12) 1069- 1072
PubMed Link to Article
Digilio  MCSarkozy  APacileo  GLimongelli  GMarino  BDallapiccola  B PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype.” Eur J Pediatr 2006;165 (11) 803- 805
PubMed Link to Article
Hanna  NMontagner  ALee  WH  et al.  Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett 2006;580 (10) 2477- 2482
PubMed Link to Article
Tartaglia  MMartinelli  SStella  L  et al.  Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 2006;78 (2) 279- 290
PubMed Link to Article
Kontaridis  MISwanson  KDDavid  FSBarford  DNeel  BG PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281 (10) 6785- 6792
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Numerous lentiginous elements scattered throughout the trunk.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Genomic structure of the PTPN11 gene and corresponding functional organization of the PTPN11-encoded SHP-2 phosphatase. Exons are represented as shaded boxes. Also shown are the main LEOPARD syndrome–associated mutations (hot spots Y279C and T468M) and our patient's R498L mutation affecting exon 13. N and C are terminal indicators; PTP indicates protein-tyrosine phosphatase; SH2, Src homology 2.

Graphic Jump Location

Tables

References

Gorlin  RJAnderson  RCBlaw  M Multiple lentigenes syndrome. Am J Dis Child 1969;117 (6) 652- 662
PubMed Link to Article
Digilio  MCConti  ESarkozy  A  et al.  Grouping of multiple-lentigines/LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet 2002;71 (2) 389- 394
PubMed Link to Article
Legius  ESchrander-Stumpel  CSchollen  EPulles-Heintzberger  CGewillig  MFryns  JP PTPN11 mutations in LEOPARD syndrome. J Med Genet 2002;39 (8) 571- 574
PubMed Link to Article
Keren  BHadchouel  ASaba  S  et al.  PTPN11 mutations in patients with LEOPARD syndrome: a French multicentric experience. J Med Genet 2004;41 (11) e117
PubMed Link to Article
Ogata  TYoshida  R PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev 2005;2 (4) 669- 674
PubMed
Kroll  JWaltenberger  J The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem 1997;272 (51) 32521- 32527
PubMed Link to Article
Chang  YCeacareanu  BDixit  MSreejayan  NHassid  A Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 and GTP-binding protein Rho. Circ Res 2002;91 (5) 390- 397
PubMed Link to Article
Maheshwari  MBelmont  JFernbach  S  et al.  PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exon 3 and 13. Hum Mutat 2002;20 (4) 298- 304
PubMed Link to Article
Conti  EDottorino  TSarkozy  A  et al.  A novel PTPN11 mutation in LEOPARD syndrome. Hum Mutat 2003;21 (6) 654
PubMed Link to Article
Sarkozy  AObregon  MGConti  E  et al.  A novelPTPN11 gene mutation bridges Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan-like/multiple giant cell lesion syndrome. Eur J Hum Genet 2004;12 (12) 1069- 1072
PubMed Link to Article
Digilio  MCSarkozy  APacileo  GLimongelli  GMarino  BDallapiccola  B PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD syndrome phenotype.” Eur J Pediatr 2006;165 (11) 803- 805
PubMed Link to Article
Hanna  NMontagner  ALee  WH  et al.  Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett 2006;580 (10) 2477- 2482
PubMed Link to Article
Tartaglia  MMartinelli  SStella  L  et al.  Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am J Hum Genet 2006;78 (2) 279- 290
PubMed Link to Article
Kontaridis  MISwanson  KDDavid  FSBarford  DNeel  BG PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem 2006;281 (10) 6785- 6792
PubMed Link to Article

Correspondence

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