Yolanda BW.indd

Ultrasonographic measurement of the nuchal translucency (NT, in the second trimester referred to as nuchal skin fold) in the fi rst trimester of pregnancy has become an established method for identifying fetuses at risk for aneuploidy.1 In the presence of a normal karyotype in fetuses with enlarged NT (>p95), there is still an increased risk of a variety of congenital abnormalities, such as cardiac defects and genetic syndromes.2;3 Detailed ultrasound examination may reveal clues as to the underlying cause of increased NT, in some cases enabling DNA analysis to confi rm a suspected syndrome. This allows genetic counseling and provides parents the possibility of making an informed decision on whether or not to continue the pregnancy. In fetuses with increased NT and a normal karyotype, Noonan syndrome should be considered, especially in the presence of cystic hygroma, cardiac defects, edema, pleural eff usions or polyhydramnion. Noonan syndrome is an autosomal dominant disorder characterized by short stature, congenital heart defects, cardiac hypertrophy, a varying degree of intellectual defi cit and distinctive facial characteristics.4 Also, distended jugular lymphatic sacs (JLS) have been reported in fetuses with Noonan syndrome.5 A delayed or disturbed jugular lymphatic development results in distension and subsequently ultrasonographic appearance of the JLS. A disturbance in lymphatic development causes nuchal edema and recently has been described as a common denominator in the pathophysiology of the increased NT.6;7 With an estimated incidence between 1:1000 and 1:2500 live births, Noonan syndrome is a relatively common cause of increased NT associated with a normal karyotype.3;8 Noonan syndrome is caused by mutations in the PTPN11 gene in approximately 50% of cases. In a recent study, PTPN11 testing based on prenatal sonographic abnormalities resulted in detection of a mutation in 16% and 2% of fetuses with cystic hygroma and increased NT, respectively.8 Recently, mutations in the SOS1-, RAF1-, MEK1 and KRASgene have been described to account for a small percentage of Noonan syndrome cases.9 Approximately 55 pregnancies with increased NT and a normal karyotype are observed annually at our center (111 times during the last two years). After counseling, prenatal analysis was requested 19 times for the PTPN11 gene and 16 times for the KRAS gene. This report covers the 3 cases where analysis of these genes led to detection of a de novo mutation and the prenatal diagnosis of Noonan syndrome. Case 1: A 37year old primigravida was referred to our hospital at 13+4 weeks gestation because of an increased NT seen at a routine fi rst-trimester ultrasound scan. Ultrasound examination confi rmed the increased NT (14.0mm), and distended JLS and bilateral pelvic dilatation of the kidneys were seen. No other anomalies were detected. Amniocentesis demonstrated a normal male karyotype. Repeated ultrasound at 16+5 weeks gestation showed a nuchal skin fold of 11.4mm, distended JLS and bilateral pleural fl uid. The renal pelvices were still dilated. Second trimester ultrasonography at 19+1 weeks gestation showed a nuchal skin fold of 10.6mm, distended JLS and unilateral left sided pleural fl uid. The bilateral dilated renal pelvices were still visible (right side 9.6mm, left side 7.7mm) with a normal bladder and a normal amount of amniotic fl uid. Low set ears were seen with three-dimensional ultrasound scanning. Fetal biometry was normal. No other structural anomalies were observed. Based on the persistence