Literature review and Discussion
NS is a hereditary multisystem disease, which is characterized by
obvious facial features, growth retardation, learning difficulties,
short stature, congenital heart disease, renal abnormalities, and
lymphatic malformations and bleeding difficulties7.
The incidence rate of NS is estimated to be between 1:1000 and 1:2500
live births8. The most common congenital heart disease
is pulmonary valve stenosis with dysplastic leaflets
(50%-62%)1. Hypertrophic obstructive cardiomyopathy
with asymmetric septal hypertrophy accounted for
20%1. Atrial septal defect is present in 6%-10% of
patients, ventricular septal defect occurs in 5%, persistent ductus
arteriosus accounted for 3%1. Other congenital heart
defects more common in NS are atrioventricular canal defects associated
with sub-aortic obstruction and abnormal mitral valve
structure2. In this case, the patient had pulmonary
valve, atrial septal defect stenosis and patent ductus arteriosus, and
the genetic diagnosis was confirmed (Fig. 1).
In NS, the affected individuals always have normal chromosome studies.
Molecular genetic analysis showed that 50% of the affected individuals
had pathogenic variants of PTPN11, with SOS1 accounting for
approximately 13%, RAF1 and RIT1 each accounting for 5%, KRAS less
than 5%, BRAF, LZTR1, MAP2K1 and NRAS less than 1%4.
This case is a mutation of RIT1 gene in c.246T > A,
p.Phe82Leu (Fig. 1). RIT1 is located in chromosome 1q22 and consists of
six exons9. Compared with the typical Noonan phenotype
associated with PTPN11 mutation, patients with RIT1 mutation had less
growth retardation and were more susceptible to
cardiomyopathy10. RIT1 belongs to RAS superfamily of
low molecular weight GTP binding proteins11. It acts
as a molecular switch of guanine nucleotide regulation in cells by
changing between active GTP binding state and inactive GDP binding
state10. RIT1 is expressed in many tissues and
throughout development11. It shares about 50%
sequence homology with RAS, has additional N-terminal extension, and
does not have C-terminal CAAX motif, a specific motif for
post-translational modification9. So far, the reported
NS related RIT1 mutations specifically affect codons 57, 82 and 95, and
lead to amino acid changes in switch I and II
regions11. These two protein motifs are involved in
the binding of nucleotides, effectors and regulators to ensure the
molecular function of RIT112. In this report, the
identified RIT1 mutation (c.246T > A, p.Phe82Leu) encodes a
change in the switch II region, which is a conserved position among
species and corresponds to RAS12. This RIT1 mutation
showed significant high ELK1 transactivation13.
Previous studies have shown that enhanced ELK transactivation has been
observed in NIH3T3 cells, which express RAF1 mutations in NS
patients14.
Chylothorax is a rare case of obstruction or interruption of lymphatic
drainage in the lower body and gastrointestinal
tract5. Lymphoid diseases are sometimes associated
with Turner, Noonan, and Trisomy 21 and Elles danlo
syndrome15. Chylothorax is characterized by lymph
nodes containing triglycerides and chylous granules in the pleural
cavity16. When the triglyceride level is higher than
1.24 mmol / L (110 mg / dl), the diagnosis is
confirmed16. In this case, the concentration of
triglyceride in pleural effusion was 2.62 mmol / L, and chyle was
positive in pleural effusion (Fig. 2 and Tab. 1). The thoracic duct
enters the thoracic cavity through the diaphragm esophageal
hiatus17. It starts from outside the pleura of the
posterior mediastinum to the right side of the spine, between the azygos
vein and the descending aorta, near the esophagus and pericardium, and
finally to the left jugular vein and subclavian vein before the
subclavian artery, vertebral artery and thyroid carotid artery
trunk17. There may be many anatomical variations in
various parts of the thoracic duct. The operation proved that the
thoracic duct stenosis was compressed by surrounding tissue. Chylothorax
was cured after removing obstruction.
To the best of our knowledge, this report of ours depicting the
refractory chylothorax due to thoracic duct stenosis in a case of NS
with RIT1 gene mutation, is the first in English literature.
Figure 1: Gene sequencing test report
According to the literature, RIT1 gene mutation can cause Noonan
syndrome and other diseases// www.omim.org/entry/609591 )Most of them
are autosomal dominant. The mutation c.246t > A and
p.Phe82leu in this sample are newly found (not included in HGMD and
gnomAD databases, gnomAD: all: 0.000%), which are located in the known
hot spot mutation region. According to the classification standard of
ACMG mutation, they can be classified as “pathogenic” mutation.
Figure 2 Chest X-ray
Large heart shadow, right lower lung exudation, right pleural effusion
Table 1 Hydrothorax examination