No mutation in the gene for Noonan syndrome, PTPN11, in 18 patients with Costello syndrome

Costello syndrome (OMIM 218040; faciocutaneoske-letal syndrome; FCS syndrome) is a rare disordercharacterized by postnatal growth deﬁciency, mentalretardation, ‘‘coarse’’ face, loose skin of the neck,hands,andfeet,cardiomyopathy,andnasalpapillomata[Costello, 1971, 1977]. To date, the causative gene forCostello syndrome is not known. Costello syndrome,cardiofaciocutaneous syndrome (CFC; MIM 115150),and Noonan syndrome (NS; MIM 163950) displaysome phenotypic similarities, prompting a controversywhether or not CFC, Noonan, and Costello syndromesrepresent different traits. Several authors have pro-posed that CFC and NS are variable manifestations ofthe same entity since both share considerable simila-rities [Fryer et al., 1991; Ward et al., 1994; Leichtman,1996; Lorenzetti and Fryns, 1996; Legius et al., 1998]. Others have argued that Noonan syndrome and CFCare similar but distinct, speciﬁc entities, whose diag-nosis is not interchangeable [Neri et al., 1991; Neri andZollino, 1996]. Costello syndrome can be added tothis group as a third disorder with clinical overlap.Wieczorek et al. [1997] compiled the clinical ﬁndings ofCFC, Noonan, and Costello syndrome and discussedthe difﬁculties of diagnosing each condition conclu-sively.TheyconcludedthattheectodermalanomaliesinCFC and Costello syndrome may help to distinguishclearly between the three disorders. The issue ofdifferential diagnosis will be solved in part followingidentiﬁcationofthecausativegeneforatleastoneentityand the absence of disease-relevant mutations in thecorresponding gene in patients with one or both of theremaining two conditions. Indeed, no mutation wasfound in one of the genes for NS, PTPN11, in 28 caseswith CFC [Ion et al., 2002] suggesting that Noonansyndrome and CFC represent separate conditions. Yet,the same question regarding Noonan and Costellosyndromes is still unanswered.PTPN11 encodes the protein tyrosine phosphataseSHP-2 [Freeman et al., 1993]. Mutations in PTPN11account for 45–50% of cases of sporadic or familial NS[Tartaglia et al., 2001, 2002]. Co-segregation of aPTPN11 mutation in a family with the Noonan-like/multiple giant-cell lesion syndrome (MIM 163955) hasalso been demonstrated [Tartaglia et al., 2002]. More-over, two groups have shown independently that multi-ple-lentigines(ML)/LEOPARDsyndrome(MIM151100)is also caused by mutations in PTPN11 [Digilio et al.,2002; Legius et al., 2002]. Although both Noonan-like/multiple giant-cell lesion and multiple-lentigines (ML)/LEOPARD syndromes were formerly considered dis-tinct disorders, current data demonstrate that (in somecases) these syndromes and NS are allelic disorders.These results also imply that mutation screening ofPTPN11 for other NS-like conditions is recommended.Thus, we considered PTPN11 a candidate gene forCostello syndrome.We collected DNA samples of 18 patients clinicallydiagnosed as Costello syndrome. Detailed phenotypicdatawereavailablefor14patientsandaresummarizedin Table I.All patients show the typical facial appearance withcoarse face, thick lips, low set ears, short neck, and fullcheeks.Pulmonicstenosisandhypertrophiccardiomyo-pathy are two frequent cardiac features of Costellosyndrome [Lin et al., 2002]. Indeed, of the 11 patients