A Novel PTPN11 Gene Mutation in a Patient with LEOPARD Syndrome

inactivation of CYLD enhances the action of NF-kB and leads phatase, nonreceptor type 11), a gene encoding a tyrosine- to increased resistance to apoptosis and carcinogenesis.6 phosphatase protein named SHP-2, with 2 particular “hot To our knowledge, this mutation has not been previ- spots” in exons 7 and 12.2-5 Despite overlapping clinical ously described. The known mutations of the CYLD gene manifestations, LS is distinct from Noonan syndrome, an- are mostly located in the C-terminal portion. other PTPN11 gene mutation–related disorder but with Germline mutations display tissue-specific function a different mutation spectrum. Herein we report the first loss. Another possibility would be that the germline mu- case to our knowledge of typical LS featuring a new tation determines the tissues where the preferred sec- PTPN11 gene mutation. ond hit occurs. When the second hit occurs in eccrine- apocrine cells, the patients become susceptible to multiple Report of a Case. A 39-year-old woman with a medical cylindromas; in hair follicle cells, the patients exhibit sus- history of deafness and a familial background of Down ceptibility to multiple cylindromas or MFT.6 syndrome in a sister was referred for evaluation of pig- Our study shows the importance of mutation screen- mentary changes that first appeared during infancy as- ing of the CYLD gene in patients affected with FC and MFT sociated with mild facial dysmorphism. Clinical exami- as well as their relatives to identify early clinical manifes- nation disclosed multiple light or dark brown macules tations. Analysis of control volunteers in this report con- of varied sizes scattered throughout her whole body sur- firms the role of this missense mutation as the cause of this face including her face, palmoplantar areas, lips, and con- syndrome. Further studies evaluating the effect of this mu- junctiva (Figure 1). There were no lentigines on the other tation in animal models must be considered. mucous membranes. Facial examination revealed hyper- telorism. Electrocardiography showed a first-degree atri- Agustıń Espanã,MD oventricular block, whereas heart ultrasound evalua- Fermin Garcıá-Amigot, PhD tion did not find any valve abnormality. Hearing Leyre Aguado, MD investigations confirmed sensorineural deafness. There Jesu´s Garcıá-Foncillas, MD were no urogenital abnormalities, endocrinopathy, or Correspondence: Dr Espan˜ a, Department of Dermatol- growth retardation. A diagnosis of LS was established ogy, University Clinic of Navarra, University of Na- based on the presence of 4 criteria. varra, PO Box 31080, Pamplona, Navarra, Spain (aespana After obtaining the patient’s consent, we undertook @unav.es). direct sequencing of the PTPN11 coding region and dis- Financial Disclosure: None reported. covered a previously undescribed (to our knowledge) het- Funding/Support: This study was supported in part by erozygous missense mutation in exon 13, namely a the Spanish Academy of Dermatology. G1493T transversion leading to an R498L change in amino Role of the Sponsor: The sponsor had no role in the de- acid sequence (Figure 2). No genetic analysis of her rela- sign and conduct of the study, in the collection, analysis tives could be carried out to establish a diagnosis of de and interpretation of data, or in the preparation review, novo or inherited mutation. or approval of the manuscript. Comment. The SHP-2 phosphatase plays several impor- 1. Clarke J, Ioffreda M, Helm KF. Multiple trichoepithelioma: a folliculosebaceous- tant roles in cellular physiologic function, mainly in cell apocrine genodermatosis. Am J Dermatopathol. 2002;24(5):402-405. proliferation, differentiation, migration, and adhe- 2. Fenske C, Banerjee P, Holden C, Carter N. Brooke-Spiegler syndrome locus 6-8 assigned to 16q12-q13. J Invest Dermatol. 2000;114(5):1057-1058. sion. This protein contains 2 main domains: a C- 3. The Human Gene Mutation Database at the Institute of Medical Genetics in terminal protein-tyrosine phosphatase (PTP) domain in- Cardiff [registration required]. http://www.hgmd.cf.ac.uk/ac/all/php ?gene=CYLD. Accessed February 9, 2007. volved in catalytic activity and 2 N-terminal Src homology 4. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in Brooke- 2 (SH2) domains interacting with the PTP domain, keep- Spiegler syndrome, familial cylindromatosis, and multiple trichoepithe- ing it folded and inactive (Figure 2).3 To our knowl- lioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005;124 (5):919-920. edge, only 7 PTPN11 mutations have been reported in 5. Regamey A, Hohl D, Liu JW, et al. The tumor suppressor CYLD interacts with patients with LS, all of them in the PTP domain in exons TRIP and regulates negatively nuclear factor kB activation by tumor necrosis 7 (Y279C and Y279S), 12 (T468M and A461T), and 13 factor. J Exp Med. 2003;198(12):1959-1964. 6. Liang YH, Gao M, Sun LD, et al. Two novel CYLD gene mutations in Chinese families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005;153(6):1213-1215.

A Novel PTPN11 Gene Mutation in a Patient With LEOPARD Syndrome

n 1969, Gorlin et al1 described an autosomal dominant syndrome encompassing multiple lentigines, I electrocardiographic abnormalities, ocular hyper- telorism, 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 het- erozygous mutations of PTPN11 (protein-tyrosine phos- Figure 1. Numerous lentiginous elements scattered throughout the trunk.

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Y279 T468M R498L

N N-SH2 C-SH2 Catalytic region (PTP) C

3 104 112 216 221 524

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.

(Q506P, Q510E, and Q510G).2,4,9-11 Two of them (Y279C 8. Maheshwari M, Belmont J, Fernbach S, et al. PTPN11 mutations in Noonan syndrome type I: detection of recurrent mutations in exon 3 and 13. Hum and T468M) represent more than 90% of the identified Mutat. 2002;20(4):298-304. changes. The mutational site in our patient is close to the 9. Conti E, Dottorino T, Sarkozy A, et al. A novel PTPN11 mutation in LEOPARD PTP-SH2 domains interacting tract and to the previ- syndrome. Hum Mutat. 2003;21(6):654. 10. Sarkozy A, Obregon MG, Conti E, et al. A novelPTPN11 gene mutation bridges ously reported mutations affecting exon 13. Accord- Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonan- ingly, this change is probably relevant as to LS patho- like/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004;12(12): 1069-1072. mechanisms. PTPN11 mutations in Noonan syndrome 11. Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B, Dallapiccola B. are likely to result in a gain of function with “perma- PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD nent” catalytic activity of the protein, whereas recent re- syndrome phenotype.” Eur J Pediatr. 2006;165(11):803-805. 12. Hanna N, Montagner A, Lee WH, et al. Reduced phosphatase activity of SHP-2 sults unexpectedly suggest that LS-related PTPN11 mu- in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. tations result in a decrease in the phosphatase function 2006;580(10):2477-2482. of SHP-2.12-14 Understanding why topographically closely 13. Tartaglia M, Martinelli S, Stella L, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am related mutations on the same gene may have opposite J Hum Genet. 2006;78(2):279-290. functional consequences but still result in close pheno- 14. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2) mutations in LEOPARD syndrome have dominant negative, not activating, types will be a rewarding challenge. effects. JBiolChem. 2006;281(10):6785-6792. Aure´lie Du-Thanh, MD He´lène Cave, PharmD, PhD Didier Bessis, MD COMMENTS AND OPINIONS Carine Puso, MD Jean-Jacques Guilhou, MD Olivier Dereure, MD, PhD Sponsorship of Graduate Medical Correspondence: Dr Dereure, Department of Dermatol- Education: One Successful Model ogy, University of Montpellier I, Hoˆpital Saint-Eloi, 80 Ave A. Fliche, 34295 Montpellier CEDEX 5, France n the March 2007 issue of the Archives, Loo et al1 dis- ([email protected]). cuss the recruitment and retention of academic der- Financial Disclosure: None reported. I matologic clinician-educators. They call for new ideas 1. Gorlin RJ, Anderson RC, Blaw M. Multiple lentigenes syndrome. Am J Dis to help provide needed support for teaching and mentor- Child. 1969;117(6):652-662. ship, suggesting that this will lead to better job satisfac- 2. Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/ LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet. tion and retention rates. It is my strong belief that robust 2002;71(2):389-394. departmental mentoring programs supported by active, 3. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewil- dedicated senior faculty members working in concert with lig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002;39(8):571-574. junior faculty members and residents is the key to increas- 4. Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with ing recruitment and retention of academic dermatologists. LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004; Implementing effective role modeling and mentor- 41(11):e117. 5. Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correla- ship involves a wide array of necessary elements that I tions in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. 2005; will not expand on other than to say that the educa- 2(4):669-674. 6. Kroll J, Waltenberger J. The vascular endothelial growth factor receptor tional environment requires the philosophical, physi- KDR activates multiple signal transduction pathways in porcine aortic en- cal, and monetary support of the leadership. From where dothelial cells. J Biol Chem. 1997;272(51):32521-32527. does the last of these, money, become available? 7. Chang Y, Ceacareanu B, Dixit M, Sreejayan N, Hassid A. Nitric oxide-induced motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2 Medical schools and institutions concerned with the and GTP-binding protein Rho. Circ Res. 2002;91(5):390-397. advancement of medicine and the development of the next

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