Costello Syndromes Research Articles

Prenatal phenotypic overlap of Costello syndrome and severe Noonan syndrome by tri‐dimensional ultrasonography

Prenatal diagnosis of multiple congenital anomalies is difficult, and usually molecular biology cannot immediately confirm the suspected syndrome. Fetal dysmorphology is useful tool in the diagnosis process, with limitations. We report the thorough prenatal investigation by 2D and 3D ultrasonography in a case of suspected Costello syndrome. Prenatal abnormalities were: increased nuchal translucency, polyhydramnios, bilateral pyelectasis and ventriculomegaly. Ultrasonographic morphological fetal face analysis found abnormal thickness of the skin in the prefrontal area, thick dysplastic ears, thick lips and deep-set creases in the hands and feet. As Costello and Noonan syndromes overlap, a PTPN11 analysis was done, with presence of a mutation (T854C). Prenatal overlap of feature of severe Noonan syndrome and Costello syndrome is confirmed, with dysmorphological similarities, due to edema of fetal skin in face and extremities.

Exclusion of PTPN11 mutations in Costello syndrome: further evidence for distinct genetic etiologies for Noonan, cardio-facio-cutaneous and Costello syndromes.

Costello syndrome (CS) is a rare, multiple congenital anomaly syndrome with characteristic dysmorphic features, cardiac anomalies and a tendency to develop certain cancers. Phenotypically there is some overlap with other genetic disorders, notably cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome (NS), suggesting that these syndromes may be allelic. We recently identified PTPN11, which encodes the non-receptor protein tyrosine phosphatase, SHP-2, as a major NS disease gene. In this report, we screened a cohort of 27 patients, with the clinical diagnosis of CS, for PTPN11 mutations using denaturing high performance liquid chromatography analysis. No mutations of the PTPN11 gene were found in the CS patients. Common polymorphisms in introns 6 and 7 and exon 8 were identified in four individuals. With our previous exclusion of PTPN11 mutations in CFC syndrome, these data suggest distinct genetic etiologies for Noonan, CFC and Costello syndromes.

PTPN11 mutations are not responsible for the Cardiofaciocutaneous (CFC) syndrome.

Cardiofaciocutaneous (CFC) syndrome is a multiple congenital anomalies/mental retardation syndrome characterized by congenital heart defects, characteristic facial appearance, short stature, ectodermal abnormalities and mental retardation. It was described in 1986, and to date is of unknown genetic etiology. All reported cases are sporadic, born to non-consanguineous parents and have apparently normal chromosomes. Noonan and Costello syndromes remain its main differential diagnosis. The recent finding of PTPN11 missense mutations in 45-50% of the Noonan patients studied with penetrance of almost 100% and the fact that in animals mutations of this gene cause defects of semilunar valvulogenesis, made PTPN11 mutation screening in CFC patients a matter of interest. We sequenced the entire coding region of the PTPN11 gene in ten well-characterised CFC patients and found no base changes. We also studied PTPN11 cDNA in our patients and demonstrated that there are no interstitial deletions either. The genetic cause of CFC syndrome remains unknown, and PTPN11 can be reasonably excluded as a candidate gene for the CFC syndrome, which we regard as molecular evidence that CFC and Noonan syndromes are distinct genetic entities.