2.6 Imaging examinations
CT showed bilateral lung exudation and pleural effusion (Figure 4). Spiral CT pulmonary angiography showed no abnormality. Echocardiography showed mild tricuspid regurgitation with elevated pulmonary artery systolic pressure(33mmHg). No clinically significant abnormality was found by emergency electrocardiography (ECG).
FINAL DIAGNOSIS
Based on the clinical signs and elevated BNP, the patient was diagnosed with acute heart failure clinically7, while pulmonary embolism was excluded based on the results of spiral CT pulmonary angiography.
TREATMENT
The patient was transferred from the ward to the intensive care unit and noninvasive positive-pressure ventilation, diuresis, and anti-infective therapy were administered immediately.
OUTCOME AND FOLLOW-UP
On the morning of postoperative day 3, all the symptoms were significantly relieved, with the oxygen saturation increasing to 100%. Plasma BNP, hs-cTnT and D-dimer levels also returned to normal. Echocardiography also showed no abnormality at this time.
DISCUSSION
MAS is a rare noninherited genetic disease characterized by polyostotic fibrous dysplasia, café-au-lait spots, and sexual precocity, which was first described by McCune and Bruch and by Albright8. In recent years, endocrine abnormalities including hyperthyroidism, growth hormone excess, and Cushing syndrome, as well as nonendocrine abnormalities such as cardiac and hepatic diseases have also been reported1, 9. Based on the genetic analysis of MAS patients, the mutation of guanine nucleotide-binding protein α-stimulating activity polypeptide (GNAS) is widely accepted as the major pathological mechanism of MAS10. The most common mutation site of GNAS is the amino acid Arg 201, which is replaced by Cys or His or Ser or Gly6, 10, 11. It is reported that the mutation of GNAS affects somatic cells but not genital cells, while the number of somatic cells mutated in specific tissues and organs varies11-14. Thus, MAS patients could present with variable clinical manifestations, which depend on the location, cell type and numbers of the mutated cells4, 9, 15.
Polyostotic fibrous dysplasia is the main skeletal manifestation of MAS, ranging from 46% to 98% according to different reports4, 16. The femur and craniofacial region are the most commonly affected. Most of the patients with MAS have at least one fracture, and even multiple fractures, especially between 6 and 12 years old4. In addition to bone fractures, fibrous dysplasia in the appendicular skeleton can lead to pain, limping, and deformities of the weight-bearing bone, while fibrous dysplasia in the craniofacial bones can lead to painless lumps or facial asymmetry. Besides, compressive syndrome and scoliosis caused by fibrous dysplasia have also been reported2. As the progression of fibrous dysplasia may bring about deformities as well as physical impairment such as limping and the need for a wheelchair, orthopedic surgical intervention is usually required for the recovery of motor functions2, 3.
Cardiovascular involvement, as a rare event in MAS patients, is one of the fatal conditions that can present as tachycardia, hypertension, cardiac hypertrophy, and even sudden death4, 9. Only one study has reported heart failure as the manifestation of cardiac involvement17. Previously, cardiac abnormalities in patients with MAS were mostly interpreted as a complication of endocrine disturbances9, 17. Subsequently, hypertrophied myocytes with Gs mutation in the macroscopically normal heart of MAS patients diagnosed with sudden death at autopsy illustrated that the mutation of heart tissue is a more convincing explanation for cardiac manifestations in MAS, rather than the complication of endocrine abnormalities4, 9. However, the underlying mechanism of cardiovascular involvement in MAS is not entirely clear. It is reported that mutation of GNAS can cause overproduction of cyclic AMP and enhanced phosphorylation of calcium channels, which subsequently increases the Ca2+ permeability of myocardial cells. As a result of intracellular Ca2+ accumulation, cardiac myocytes are continuously overactivated and cause increased heart rate and myocardial contractility, which eventually induce cardiac dysfunction[4,20].
According to the acute heart failure assessment reported by the literature, our patient could be diagnosed with acute heart failure based on elevated NT-proBNP, interstitial edema, dyspnea and absence of fever18. For differential diagnosis, pulmonary embolism has been excluded through Spiral CT pulmonary angiography. Normal ECG and no chest pain also do not agree with acute coronary syndrome or arrhythmia due to reduced hemoglobin postoperatively. Pulmonary complications were not consistent with extremely high BNP. Considering Swan-Ganz catheter or nuclear imaging is only recommended for non-classical acute heart failure like without BNP elevated or the treatment is not effective19, we did not perform them on our patient.
To the best of our knowledge, postoperative acute heart failure in a young patient without a history of cardiac disease and cardiac morphology abnormality has not yet been reported. In consideration of the fact that macroscopic findings of the Gs mutated heart are often inconspicuous in the clinic4, as well as the impossibility of acute heart failure for a patient without a history of cardiovascular abnormalities at such a young age, latent cardiovascular involvement of MAS seems to be a reasonable interpretation for the acute heart failure of the present patient.
We proposed two potential mechanisms for acute heart failure in this young patient with limited fluid replacement volume based on the known cardiotoxicity of cAMP and Ca2+20. Firstly, long-term cAMP overload may induce myofilament calcium desensitization of the cardiac myocytes through increased protein kinase A. Therefore, the desensitized cardiac myocytes cannot respond effectively to the increased calcium influx to enhance the cardiac contractibility when the fluid load increases21, 22. Secondly, long-term Ca2+ overload may have a negative impact on the compliance of the heart due to the hypertrophied myocytes and increased myocardial contractility23. However, we admit that further investigation is required to explore further the exact mechanism.
The present report was limited because we could not perform genetic analysis of cardiomyocytes due to regulatory and ethical concerns.
CONCLUSIONS
Many patients with MAS are admitted to orthopedic departments for surgical intervention. Therefore, it is important for orthopedic surgeons to be aware of polyostotic fibrous dysplasia and other rare but fatal manifestations, such as cardiac involvement. To the best of our knowledge, our report represents the first case of a young woman with MAS and acute heart failure after proximal femur osteotomy, with no cardiovascular abnormality or history of cardiovascular disease. As latent cardiovascular involvement of MAS was considered to be the major cause of this case, we recommend more detailed preoperative cardiovascular screening for MAS patients. We believe that this case report and the literature review will help orthopedic surgeons make a more reasonable prognostic assessment, and subsequently reduce the risk of medical dispute by further understanding this rare but fatal event of MAS.