Prenatal sonographic documentation of cystic hygroma regression in Noonan syndrome

Donnenfeld, Alan E.; Nazir, Munir; Sindoni, Frank; Librizzi, R.

doi:10.1002/ajmg.1320390418

Cited by 23 publications

(14 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…As demonstrated in this study, polymorphisms or mutations in the Ras genes and other genes encoding proteins that participate in Ras/MAPK signalling are probable candidates. Furthermore, lymphedema, lymphangioma/hygroma and chylothorax have been reported in Noonan and cardio-facio-cutaneous syndromes caused by germline mutations in KRAS and other genes that encode proteins involved in the Ras/MAPK signalling pathway (Chan et al, 2002;Donnenfeld et al, 1991;Evans et al, 1991;Witt et al, 1987). Our mouse models that overexpress Hras using an artificial gene construct might not sufficiently model human diseases where physiological upregulation of Ras or expression of weak-activating mutant forms of Ras proteins occur.…”

Section: Research Articlementioning

confidence: 99%

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

2010

View full text Add to dashboard Cite

SUMMARYMammalian Ras, which is encoded by three independent genes, has been thought to be a versatile component of intracellular signalling. However, when, where and how Ras signalling plays essential roles in development and whether the three Ras genes have overlapping functions in particular cells remain unclear. Here, we show that the three Ras proteins dose-dependently regulate lymphatic vessel growth in mice. We find that lymphatic vessel hypoplasia is a common phenotype in Ras compound knockout mice and that overexpressed normal Ras in an endothelial cell lineage selectively causes lymphatic vessel hyperplasia in vivo. Overexpression of normal Ras in lymphatic endothelial cells leads to sustained MAPK activation, cellular viability and enhanced endothelial network formation under serum-depleted culture conditions in vitro, and knockdown of endogenous Ras in lymphatic endothelial cells impairs cell proliferation, MAPK activation, cell migration and endothelial network formation. Ras overexpression and knockdown result in up-and downregulation of vascular endothelial growth factor receptor (VEGFR) 3 expression, respectively, in lymphatic endothelial cells in vitro. The close link between Ras and VEGFR3 in vitro is consistent with the result that Ras knockout and transgenic alleles are genetic modifiers in lymphatic vessel hypoplasia caused by Vegfr3 haploinsufficiency. Our findings demonstrate a cooperative function of the three Ras proteins in normal development, and also provide a novel aspect of VEGFR3 signalling modulated by Ras in lymphangiogenesis.

show abstract

Section: Research Articlementioning

confidence: 99%

H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice

2010

View full text Add to dashboard Cite

show abstract

“…In view of the difficulty to establish a postnatal diagnosis, it is not surprising that despite the distinctive phenotype and the common association with congenital lymphatic and cardiac abnormalities, only six reports of prenatal sonographic features of Noonan syndrome were found in the literature [Zarabi et al, 1983;Witt et al, 1987;Benacerraf et al, 1989;Izquierdo et al, 1990;Donnefeld et al, 1991;Sonesson et al, 1992]. In only two reports was the diagnosis of Noonan syndrome suspected during pregnancy [Benacerraf et al, 1989;Donnefeld et al, 1991], whereas other authors described sonographic findings retrospectively in patients diagnosed postnatally. In the 12 reported cases that had prenatal sonographic evaluation, skin edema was present in two, generalized hydrops in five, and nuchal cystic hygroma of the septated type and hydramnios in all 12.…”

Section: Discussionmentioning

confidence: 88%

“…Early sonographic data, obtained between 12 and 14 weeks of gestation, were available in three cases; two had cystic hygroma and one was normal. In one of the two, cystic hygroma subsequently resolved and left a skin web recognized by ultrasound and confirmed after delivery [Donnefeld et al, 1991].…”

Section: Discussionmentioning

confidence: 97%

“…Lymphedema, cystic hygroma, and cardiomyopathy during late stages of gestation were reported in fetuses with Noonan syndrome [Zarabi et al, 1983;Witt et al, 1987;Benacerraf et al, 1989;Izquierdo et al, 1990;Donnefeld et al, 1991;Sonesson et al, 1992]. Recently, with the introduction of early ultrasonographic screening for fetal aneuploidy, fetuses with "nuchal translucency" and normal karyotype were occasionally found to have Noonan syndrome [Johnson et al, 1993;Trauffer et al, 1994;Souka et al, 1998].…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Noonan syndrome: A cryptic condition in early gestation

et al. 2000

View full text Add to dashboard Cite

Noonan syndrome is one of the most common of genetic syndromes and manifests at birth, yet it is usually diagnosed during childhood. Although prenatal diagnosis of Noonan syndrome is usually not possible, in a few cases the ultrasonographic findings suggested the diagnosis in utero. Reported sonographic clues include septated cystic hygroma, hydrothorax, polyhydramnios, and cardiac defects, such as pulmonic stenosis and hypertrophic cardiomyopathy. During a 6-year period, 46,224 live-born infants were delivered at the Chaim Sheba Medical Center. Seven newborn infants and four fetuses were found to have Noonan syndrome. One fetus showed transient nuchal translucency of 4 mm and bilateral neck cysts at the 13th gestational week. Both findings resolved spontaneously by the 18th gestational week, but during the third trimester this fetus developed hydrothorax, skin edema, and polyhydramnios. In the three other fetuses, first- and second-trimester ultrasonographic findings were normal, and the diagnosis of Noonan syndrome was suggested only during the third trimester. All three fetuses had polyhydramnios and skin edema. A cardiac malformation, hydrothorax, and a large head were present in one fetus. Sonographic facial findings were investigated. In all four fetuses posteriorly angulated, apparently low-set ears and depressed nasal bridge were identified. Wide nasal base was seen in two fetuses. In two fetuses, persistent opening of the fetal mouth was interpreted as fetal hypotonia. One fetus developed progressive postnatal hypertrophic cardiomyopathy and in one case, pulmonic stenosis became apparent at age 6 months. This small series suggests that Noonan syndrome has an evolving phenotype during in utero and postnatal life. Amelioration of early nuchal region findings and late onset of the more "typical" ultrasonographic changes may limit early prenatal detectability.

show abstract

“…This is particularly so when the fetus is found to have a heart defect characteristic of this condition (such as our case 4). A variety of prenatal presentations of Noonan syndrome have been reported (Benacerraf et al, 1989;Langer et al, 1990;Izquierdo et al, 1990;Donnenfeld et al, 1991;Johnson et al, 1993;Schulman et al, 1994;Trauffer et al, 1994;Brady et al, 1998). A history of polyhydramnios may be obtained in 33 per cent of mothers of a child with Noonan syndrome (Sharland et al, 1992).…”

Section: Discussionmentioning

confidence: 95%