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J Med Genet 2003;40:704-708 doi:10.1136/jmg.40.9.704
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Correlation between PTPN11 gene mutations and congenital heart defects in Noonan and LEOPARD syndromes

  1. A Sarkozy3,*,
  2. E Conti3,*,
  3. D Seripa3,
  4. M C Digilio4,
  5. N Grifone3,
  6. C Tandoi1,
  7. V M Fazio3,
  8. V Di Ciommo5,
  9. B Marino2,
  10. A Pizzuti1,
  11. B Dallapiccola3
  1. 1Department of Experimental Medicine and Pathology, University “La Sapienza”, Rome, Italy
  2. 2Section of Paediatric Cardiology, Institute of Paediatrics, University “La Sapienza”
  3. 3CSS Hospital, IRCCS, San Giovanni Rotondo, and CSS-Mendel Institute, Rome
  4. 4Division of Medical Genetics, Bambino Gesù Hospital, IRCCS, Rome
  5. 5Epidemiology Unit, Bambino Gesù Hospital
  1. Correspondence to:
 Dr Emanuela Conti CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy;
 e.conti{at}css-mendel.it

    Noonan syndrome (MIM 163950), an autosomal dominant disorder with an estimated prevalence of 1/1000–2500 at birth, is characterised by short stature, facial anomalies, pterygium colli, and congenital heart disease.1,2 Although pulmonary valve stenosis with dysplastic leaflets, hypertrophic cardiomyopathy, and atrial septal defects (ASD) are the most common congenital heart defects in Noonan syndrome,3 a broad spectrum of cardiac phenotypes has been recognised.2–6 About half the affected individuals have PTPN11 gene mutations.7–9 This gene, which maps to chromosome 12q22-qter,10 encodes for the human SH2 domain containing protein tyrosine phosphatase (SHP2).11PTPN11 gene mutations have also been detected in multiple lentigines/LEOPARD syndrome (multiple lentigines, ECG conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness; ML/LS, MIM 151100),12,13 in Noonan-like/multiple giant cell lesion syndrome (MIM 163955),8 in two families presumably affected by cardio-facio-cutaneous syndrome (CFCS, MIM 115150),14 but not in sporadic CFCS.15 The clinical and genetic heterogeneity of these disorders suggests a possible relation between different PTPN11 gene mutations and distinct clinical features. A genotype–phenotype correlation study in Noonan syndrome found an association between pulmonary stenosis and PTPN11 mutations.8 Our aim in this study was to screen a large cohort of patients with Noonan syndrome and ML/LS in order to expand the genotype–phenotype correlation analysis, with particular emphasis on cardiac diseases.

    Key points

    • Noonan syndrome and multiple lentigines/LEOPARD syndrome (ML/LS) are associated with a broad spectrum of congenital heart defects in 50–80% of patients. Many patients with Noonan syndrome and most with ML/LS harbour mutations in the PTPN11 gene.

    • The occurrence of PTPN11 gene mutations was investigated in 71 patients with Noonan syndrome and 13 with ML/LS, including 73 with congenital heart defects. A genotype-phenotype correlation analysis was undertaken, with major emphasis on …

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