Fabrice Cuillier, MD*; E. Faller, MD*; I. Bourdarias, MD*; P. Lemaire, MD**; M. Deshayes, MD**; A. Berta***.

Definition

Noonan syndrome is characterized by short stature, typical facial appearance, a broad or webbed neck and cardiac anomalies (especially  pulmonary stenosis, hypertrophic cardiomyopathy, and ventricular septal defect) [1]. Diagnosis of the Noonan syndrome is often difficult to make, because of the high variability of clinical symptoms [2, 3]. According to some authors, Noonan syndrome was never diagnosed prenatally.

In our case the definitive diagnosis was also done postnatally.

Case report

A 35-year-old, G3P2, with noncontributive history, first time presented at 13 weeks of pregnancy. Our ultrasound examination revealed an increased thickness of the nuchal translucency (4 mm) (Figure N°1A, 1B, 1C, 1D) and dilated cervical lymphatics of the fetus. At 16 weeks an amniocentesis demonstrated normal karyotype (46, XY). Maternal viral studies were negative. At 18 and 22 weeks the ultrasound investigation of the fetus was normal and no anomalies were observed. At 33 weeks the fetal echocardiography demonstrated a mildly dysplastic aortic valve (Figure N°5, N°6). At 36 weeks the ultrasound found an turbulent color Doppler flow at the level of the aortic valves (Figure N°7A, 7B, 7C, 7D). A moderate cardiomegaly was also present. At 38 weeks the findings were the same and the aorta appeared to be stenotic at the level of the semilunar valves. The neonate was delivered a few hours after ultrasonographic examination with the Apgar score 4 and 4 in the first and fifth minute, with apparent cyanosis, which remained unchanged despite of the oxygen therapy. The neonate developed a pulmonary hypertension requiring the high pressure ventilation (Figure N°8A, 8B). The postnatal echocardiography confirmed the aortic valves" dysplasia and also discovered a moderate pulmonary valve stenosis. Clinical appearance of the neonate demonstrated some of the features of the Noonan syndrome, with the low set dysplastic ears, widely spread nipples and exophtalmia. Thrombocytopenia was also present. The diagnosis of the Noonan syndrome was confirmed by the gene PTPN11 study.

Images 1, 2: 13 weeks of pregnancy; Image 1 shows a sagittal section through the fetal neck with increased thickness of the nuchal translucency (4.1 mm). Image 2 shows a transverse scan through the fetal neck with dilated lymphatics.

Images 3, 4: Image 3 represents 13 weeks of pregnancy showing a transverse scan through the fetal neck with edema of the dorsal part. Image 4 represents 33 weeks of pregnancy. Image shows right (left part of the image) and left (right part of the image) outflow tracts of the heart with narrowing at the level of aortic semilunar valves.

Images 5, 6: 33 weeks of pregnancy; gray scale (Image 5) and color Doppler (Image 6) images show the left outflow tract of the heart with narrowing at the level of aortic semilunar valves.

Images 7, 8: Postnatal appearance of the neonate.

Video 1: Video demonstrates the difference between the right and left outflow tract of the heart, with narrowing of the aorta at the level of semilunar valves.

Synonyms

Turner Syndrome with normal karyotype; Pseudo Turner syndrome; Male Turner syndrome; Ullrich syndrome [4].

History

Noonan syndrome was first described by Noonan and Ehmke in 1963. Jacqueline Noonan described 19 cases of this syndrome in 1968, which were similar to the disorder described by Turner, but with normal karyotype [5].

Prevalence

The incidence of the Noonan syndrome is between 0.5 - 1:1000 [4].

Etiology

Unknown.

Pathogenesis

Noonan is inherited in an autosomal dominant manner, although many cases are sporadic [3]. Inheritance is more common through the maternal line, probably due to the high incidence of male subfertility [1-3]. 40% of cases are caused by mutations of PTPN11 gene. Some cases of the Noonan syndrome can arise de novo, so many cases are in fact sporadic. The gene responsible for the Noonan syndrome is located in the long arm of the chromosome 12 [5].  

Recurrence risk

According to Nisbet, the recurrence risk is 5%, when the parents have only possible or no signs of Noonan syndrome [3].

Sonographic findings

Although the phenotype is distinctive and the syndrome may manifest at birth, the mean age when the Noonan syndrome is diagnosed is 9 years, as the dysmorphic features can be subtle. 

The prenatal ultrasound findings reported in Noonan syndrome include accumulation of nuchal fluid, femur lengths at or just below the lower end of the normal range, pleural effusions, and renal anomalies. The most common prenatal features are polyhydramnios (58%), cystic hygroma (42%), increased thickness of the nuchal translucency and fetal hydrops (33%). Cardiac anomalies are present in 60% of cases: including left ventricular hypertrophy (25%), pulmonary stenosis (19%), atrial septal defect (10%) or dysplastic pulmonary valve in 7% [5].

During the prenatal period the symptoms may not be fully blown and sometimes can be visible only in a restricted time frame or are unspecific, and will not lead to an unequivocal diagnosis.

The diagnosis of the Noonan syndrome is usually made postnatally, unless a parent has an obvious Noonan syndrome phenotype. Nisbet et al (1999) demonstrate the diversity of the prenatal presentation. They propose to think about the diagnosis of the Noonan syndrome when faced with a fetus with a normal karyotype, but with varying degrees of edema or hydrops, with short femurs.

Nevertheless, several authors argue that the prenatal diagnosis of the Noonan syndrome is difficult and inefficient.

Differential diagnosis

Turner syndrome: excluded in boys and by karyotype; Leopard syndrome: association of multiples lentigines with pulmonary stenosis and deafness; Costello syndrome; Escobar syndrome; Trisomy 21.

Associated anomalies

Ductal agenesis with no intrahepatic portion are described associated with Noonan Syndrome and in these cases drainage was possible directly into the right atrium, inferior vena cava or inferior vena cava via the iliac vein [4].

Ductal agenesis with iliac connection is a classic sign of Noonan syndrome. Drainage can also be directly into the right atrium, inferior vena cava or iliac vein.

Prognosis

According to Shah at al (1999), delayed gastrointestinal motor development is responsible for feeding problems [6]. Prognosis is essentially dependent on congenital cardiovascular abnormalities. Without major cardiac anomalies, normal life expectancy can be presupposed.

Management

Standard prenatal care is not altered when continuation of the pregnancy is chosen [6]. Nevertheless, termination of pregnancy is possible, if serious cardiac anomalies are present. When a parent has Noonan syndrome or when a couple has had a child with Noonan syndrome before, detailed prenatal sonography should be done in the first, second and third trimester focused to the cardiac anomalies. The identification of increased nuchal fluid or hydrops in combination with borderline femurs" length and cardiac anomalies (especially pulmonary stenosis or dysplastic aortic valves), should also evoke a possibility of Noonan syndrome in the differential diagnostic consideration. Parents should be referred to a genetic counseling. 

References

1. Bradley E., Kean L., Twining P., James D. Persistent right umbilical vein in a fetus with Noonan’s syndrome: a case report. Ultrasound Obstet Gynecol 2001; 17: 76-8.
2. Schlüter G., Steckel M., Schffmann H., Harms K., Viereck V., Emons G., Burfeind P., Pauer H.U. Prenatal DNA diagnosis of Noonan syndrome in a fetus with massive hygroma coli, pleural effusion and ascites. Prenat Diagn 2005; 25: 574-6.
3. Nisbet D.L., Griffin D.R., Chitty L.S. Prenatal features of Noonan syndrome. Prenatal Diagn 1999; 19: 642-7.
4. Jeanty P., Silva S.R., Leite J. Noonan Syndrome. Thefetus.net 2006-01-18.
5. Burglen L. Le syndrome de noonan. Aspects anténatals, devenir postnatal, aspects génétiques et diagnostiques. Med Foet Echo Gynecol 2002; 50: 9-12. 
6. Shah N., Rodriguez M., St-Louis D., Kindley K., Milla M.J. Feeding difficulties and foregut dysmotility in Noonan’s syndrome. Arch Dis Child 1999; 81: 28-31.