Download PDF
J Pediatr Genet 2020; 09(04): 246-251
DOI: 10.1055/s-0039-3400226
Case Report
Georg Thieme Verlag KG Stuttgart · New York

LEOPARD Syndrome with PTPN11 Gene Mutation in Three Family Members Presenting with Different Phenotypes

Nuha Alfurayh
1   Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
,
Fahad Alsaif
1   Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
,
Nouf Alballa
1   Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
,
Leena Zeitouni
1   Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
,
Khushnooda Ramzan
2   Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
,
Faiqa Imtiaz
2   Department of Genetics, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
,
Abdullah Alakeel
1   Department of Dermatology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
› Author Affiliations
Further Information

Publication History

05 June 2019

04 October 2019

Publication Date:
15 November 2019 (online)

    Permissions and Reprints

Abstract

LEOPARD syndrome (LS) is a rare autosomal dominant disorder that is characterized by multiple lentigines and various congenital anomalies. The clinical diagnosis of LS requires molecular confirmation. The most frequently reported mutations in LS patients are in the protein tyrosine phosphatase nonreceptor type 11 gene, PTPN11. Herein, we report the cases of three family members from two generations who are affected by LS and all carry the PTPN11 mutation c.836A > G (p.Tyr279Cys), identified by next-generation sequencing, while exhibiting different phenotypes.

Keywords

LEOPARD syndrome - PTPN11 - multiple lentigines
 

  • References

  • 1 Gorlin RJ, Anderson RC, Blaw M. Multiple lentigenes syndrome. Am J Dis Child 1969; 117 (06) 652-662
    CrossrefPubMedGoogle Scholar
  • 2 Gorlin RJ, Anderson RC, Moller JH. The Leopard (multiple lentigines) syndrome revisited. Birth Defects Orig Artic Ser 1971; 07 (04) 110-115
    PubMedGoogle Scholar
  • 3 Zhang J, Shen J, Cheng R. , et al. Identification of a PTPN11 hot spot mutation in a child with atypical LEOPARD syndrome. Mol Med Rep 2016; 14 (03) 2639-2643
    CrossrefPubMedGoogle Scholar
  • 4 Coppin BD, Temple IK. Multiple lentigines syndrome (LEOPARD syndrome or progressive cardiomyopathic lentiginosis). J Med Genet 1997; 34 (07) 582-586
    CrossrefPubMedGoogle Scholar
  • 5 Rodríguez-Bujaldón A, Vazquez-Bayo C, Jimenez-Puya R. , et al. LEOPARD syndrome: what are café noir spots?. Pediatr Dermatol 2008; 25 (04) 444-448
    CrossrefPubMedGoogle Scholar
  • 6 Zhang J, Cheng R, Liang J, Ni C, Li M, Yao Z. Lentiginous phenotypes caused by diverse pathogenic genes (SASH1 and PTPN11): clinical and molecular discrimination. Clin Genet 2016; 90 (04) 372-377
    CrossrefPubMedGoogle Scholar
  • 7 Sarkozy A, Digilio MC, Dallapiccola B. Leopard syndrome. Orphanet J Rare Dis 2008; 3 (01) 13
    CrossrefPubMedGoogle Scholar
  • 8 Kalev I, Muru K, Teek R. , et al. LEOPARD syndrome with recurrent PTPN11 mutation Y279C and different cutaneous manifestations: two case reports and a review of the literature. Eur J Pediatr 2010; 169 (04) 469-473
    CrossrefPubMedGoogle Scholar
  • 9 Lodish MB, Stratakis CA. The differential diagnosis of familial lentiginosis syndromes. Fam Cancer 2011; 10 (03) 481-490
    CrossrefPubMedGoogle Scholar
  • 10 Motegi S, Yokoyama Y, Ogino S. , et al. Pathogenesis of multiple lentigines in LEOPARD syndrome with PTPN11 gene mutation. Acta Derm Venereol 2015; 95 (08) 978-984
    CrossrefPubMedGoogle Scholar
  • 11 Pandit B, Sarkozy A, Pennacchio LA. , et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet 2007; 39 (08) 1007-1012
    CrossrefPubMedGoogle Scholar
  • 12 Sarkozy A, Carta C, Moretti S. , et al. Germline BRAF mutations in Noonan, LEOPARD, and cardiofaciocutaneous syndromes: molecular diversity and associated phenotypic spectrum. Hum Mutat 2009; 30 (04) 695-702
    CrossrefPubMedGoogle Scholar
  • 13 Koudova M, Seemanova E, Zenker M. Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. Eur J Med Genet 2009; 52 (05) 337-340
    CrossrefPubMedGoogle Scholar
  • 14 Zeisler EP, Becker SW. Generalized lentigo: its relation to systemic nonelevated nevi. Arch Derm Syphilol 1936; 33 (01) 109-125
    PubMedGoogle Scholar
  • 15 Voron DA, Hatfield HH, Kalkhoff RK. Multiple lentigines syndrome. Case report and review of the literature. Am J Med 1976; 60 (03) 447-456
    CrossrefPubMedGoogle Scholar
  • 16 Nemes E, Farkas K, Kocsis-Deák B. , et al. Phenotypical diversity of patients with LEOPARD syndrome carrying the worldwide recurrent p.Tyr279Cys PTPN11 mutation. Arch Dermatol Res 2015; 307 (10) 891-895
    CrossrefPubMedGoogle Scholar
  • 17 Kato H, Yoshida R, Tsukamoto K. , et al. Familial cases of atypical clinical features genetically diagnosed as LEOPARD syndrome (multiple lentigines syndrome). Int J Dermatol 2010; 49 (10) 1146-1151
    CrossrefPubMedGoogle Scholar
  • 18 Bertola DR, Pereira AC, Passetti F. , et al. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A 2005; 136 (03) 242-245
    PubMedGoogle Scholar
  • 19 Martínez-Quintana E, Rodríguez-González F. LEOPARD syndrome: clinical features and gene mutations. Mol Syndromol 2012; 3 (04) 145-157
    PubMedGoogle Scholar
  • 20 Wang Y, Chen C, Wang DW. Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han. Int J Cardiol 2014; 174 (03) e101-e104
    CrossrefPubMedGoogle Scholar
  • 21 Tartaglia M, Gelb BD. Noonan syndrome and related disorders: genetics and pathogenesis. Annu Rev Genomics Hum Genet 2005; 6: 45-68
    CrossrefPubMedGoogle Scholar
  • 22 Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet 2002; 39 (08) 571-574
    CrossrefPubMedGoogle Scholar
  • 23 Edouard T, Combier JP, Nédélec A. , et al. Functional effects of PTPN11 (SHP2) mutations causing LEOPARD syndrome on epidermal growth factor-induced phosphoinositide 3-kinase/AKT/glycogen synthase kinase 3beta signaling. Mol Cell Biol 2010; 30 (10) 2498-2507
    CrossrefPubMedGoogle Scholar
  • 24 Marin TM, Keith K, Davies B. , et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest 2011; 121 (03) 1026-1043
    CrossrefPubMedGoogle Scholar
  • 25 Tajan M, Batut A, Cadoudal T. , et al. LEOPARD syndrome-associated SHP2 mutation confers leanness and protection from diet-induced obesity. Proc Natl Acad Sci U S A 2014; 111 (42) E4494-E4503
    CrossrefPubMedGoogle Scholar
  • 26 Kontoes PP, Vlachos SP, Marayiannis KV. Intense pulsed light for the treatment of lentigines in LEOPARD syndrome. Br J Plast Surg 2003; 56 (06) 607-610
    CrossrefPubMedGoogle Scholar
  • 27 Lee HJ, Chung HJ, Cho YH, Chung KY. A case of LEOPARD syndrome. Korean J Dermatol 2005; 43 (07) 949-952
    PubMedGoogle Scholar