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