American Journal of Medical Genetics 130A:378–383 (2004) Clinical Variability in a Noonan Syndrome Family With a New PTPN11 Gene Mutation De ´ bora Romeo Bertola, 1 * Alexandre C. Pereira, 2 Paulo S.L. de Oliveira, 2,3 Chong A. Kim, 1 and Jose ´ Eduardo Krieger 2 1 Genetics Clinic Unit, Instituto da Crianc ¸a do Hospital das Clı´nicas, University of Sa ˜ o Paulo, Sa ˜ o Paulo, Brazil 2 Laborato ´rio de Gene ´tica e Cardiologia Molecular, Heart Institute (InCor), University of Sa ˜ o Paulo, Sa ˜ o Paulo, Brazil 3 Disciplina de Informatica Me ´dica, Medical School, University of Sa ˜ o Paulo, Sa ˜ o Paulo, Brazil Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dys- morphism, short and/or webbed neck, heart defects, and cryptorchidism in males. The gene responsible for the disorder (PTPN11) was recently identified, and explains 30–50% of the cases clinically diagnosed as NS. Cardiofaciocu- taneous (CFC) syndrome, a similar but distinct entity, is characterized by relative macrocephaly, characteristic facial appearance, ectodermal abnormalities (sparse and friable hair, sparse eyebrows, hyperkeratotic skin), congenital heart defects, and growth and mental retardation. We describe on a young woman who presents clinical features of NS (short stature, triangular facies, with dowslanting palpebral fissures and apparent hypertelorism, webbed neck, pulmonary stenosis, bleeding diathesis, prominent corneal nerves), but with a more prominent ectodermal involve- ment (sparse and very coarse hair, sparse eye- brows and eyelashes) and developmental delay/ mental retardation, which are characteristic of CFC patients. Sequencing of the PTPN11 gene showed a T411M substitution, not previously described in patients with NS. The same mutation was found in her mother and older sister, not initially considered to be affected by NS, but with very subtle clinical findings compatible with this diagnosis. Molecular dynamic studies indicate that this new mutation, similar to other pre- viously described mutations, favors a more active protein conformation. However, the main disrup- tive effect is not directly in the catalytic domain, suggesting that the location of this mutation could make the protein more susceptible to gene–gene or gene – environment interactions. Atypical cases of NS should be screened for mutations in the PTPN11 gene and in the case of a positive result, first-degree relatives should also be tested for the specific mutation. ß 2004 Wiley-Liss, Inc. KEY WORDS: PTPN11; autosomal dominant dis- order; Noonan syndrome INTRODUCTION Noonan syndrome (NS) is an autosomal dominant disorder comprising short stature, facial dysmorphisms (ocular hyper- telorism, downslanting palpebral fissures, palpebral ptosis, high arched palate, and dental malocclusion), short and/or webbed neck, heart defects, mainly valvar pulmonary stenosis, sternal deformity, and cryptorchidism in males [Noonan, 1994]. Besides these broad clinical findings, as is common in autosomal dominant disorders, there is a variable clinical expressivity in affected persons, even within the same family. Due to this clinical variability, diagnosis is not always straightforward. Allanson et al. [1985] showed that the facial features in NS change with age and the typical findings are more evident in childhood. In adults, the facial features could be subtle and a diagnosis of NS in these patients can be difficult. This fact is clinically relevant, especially when the recurrence risk for a future child of parents of a NS patient have to be accessed. This risk ranges from less than 1% (if none of the parents are affected) to 50% when one of them is affected. In order to facilitate the diagnosis of NS, clinical criteria were set forth by some authors [Duncan et al., 1981; van der Burgt et al., 1994]. These latter authors, considering that there is an important clinical variability in NS and the facial features are not always characteristic, especially in adults, included in their clinical criteria the presence of a suggestive facies, besides the typical one. With the recently characterization of the gene responsible for NS—PTPN11 [Tartaglia et al., 2001], it is now possible to progress on this issue. The PTPN11 gene, localized in the long arm of chromosome 12 (12q24.1), is responsible for 30% [Kosaki et al., 2002; Musante et al., 2002] to 50% [Tartaglia et al., 2002] of the cases clinically diagnosed as NS, confirming that this syndrome is a heterogeneous disorder. Tartaglia et al. [2002] screened the parental DNA of 43 apparently sporadic NS cases for PTPN11 gene mutations and only one parent was identified as carrying a mutation, supporting the idea that a small proportion of affected NS individuals have a very mild phenotype. Further application of molecular studies focus on the characterization of syndromes that have an obvious clinical overlap with NS, such as cardiofaciocutaneous (CFC) syn- drome, LEOPARD syndrome, Noonan-like/multiple giant cell lesion syndrome, and Costello syndrome. For several years there has been discussion in the literature whether these syndromes are really distinct entities, allelic conditions or part of the spectrum of NS. It is now known that the PTPN11 gene is also responsible for LEOPARD syndrome [Digilio et al., 2002; Legius et al., 2002] and Noonan-like/multiple giant cell lesion syndrome [Tartaglia et al., 2002]. On the other hand, no muta- tion in PTPN11 has been shown so far in patients with CFC syndrome [Ion et al., 2002; Musante et al., 2002; Kavamura et al., 2003] or Costello syndrome [Tartaglia et al., 2003]. We report on a novel PTPN11 gene mutation in a family with important clinical variability, where the proband has *Correspondence to: Dr. De ´bora Romeo Bertola, Av Dr. E ´ neas Carvalho de Aguiar, 647, Unidade de Gene ´tica Clı ´nica do Instituto da Crianc ¸a—HC-FMUSP, CEP: 05403-900, Sa ˜ o Paulo, SP, Brazil. E-mail: drbertola@attglobal.net Received 13 August 2003; Accepted 26 April 2004 DOI 10.1002/ajmg.a.30270 ß 2004 Wiley-Liss, Inc.