Medical history and physical examination

The study received ethical approval from the Ethics Committee of the West China Second Hospital of Sichuan University (approval no. 2014-034). Written informed consent was obtained from the patient’s parents prior to conducting whole-exome sequencing and including the patient’s clinical and imaging details in publications.

The proband, a 15-year-old male, was admitted to our hospital with a history of recurrent cough, palpitations, chest distress, and vomiting persisting for more than 10 days. These symptoms appeared to worsen in recent days. The patient also experienced a significant reduction in activity tolerance and severe dull chest pain attacks. Walking a distance of only 100–200 m became challenging, and climbing stairs was impossible. Additionally, the patient experienced shortness of breath after mild activity. The nature of the chest pain was distinct from that of acute coronary artery syndrome, as it lacked qualities such as aching, tightness, and radiating discomfort. The patient also reported feeling exhausted with decreased food intake. There were no accompanying fever, syncope, or diarrhoea. The patient denied any history of cardiovascular diseases and rheumatic disorders, as well as any recent symptoms of viral or bacterial infections.

No surface wounds, particularly in the chest area, indicated the absence of accidental injuries. The patient had a breathing rate of 20–35 breaths per minute. Bilateral lung respiratory movements were symmetrical, with rough breath sounds and significantly apparent bilateral wet rales. The apex of the heart was displaced to the lower left, and a lift sensation was present in the precordial area. Severe cardiac enlargement was observed, accompanied by an extremely dull heart sound. Level I systolic and diastolic murmurs were audible at the aortic valve auscultation site. The abdomen was soft, the liver was palpable 3 cm below the subcostal margin and 1 cm below the xiphoid process, with a medium texture, and the spleen was not palpable below the subcostal margin. Muscle strength and tension in all four extremities were normal, and no pathological or meningeal irritation signs were observed.

Furthermore, the patient’s parents denied any positive family history of cardiac events, cardiovascular diseases, hypertension, coronary artery diseases, diabetes, or obesity among their family members. No inherited diseases, including cardiomyopathies and metabolic disorders, were identified within the family.

Imaging and laboratory examinations

Initial laboratory tests revealed a standard range of routine blood cell test and blood gas analysis. The C-reactive protein increased to 58.0 mg/L (n.v. < 8.0 mg/L). Besides, the results of hepatic and renal function yielded significant elevation of alanine aminotransferase (310 U/L, n.v. < 49 U/L) and raised aspartate aminotransferase (710 U/L, n.v. < 40 U/L). At the same time, other parameters were primarily located in a normal range. Additionally, the significant elevation of serum cardiac troponin I (1.325 ug/L, n.v. < 0.06 µg/L) and B-type natriuretic peptide (20,276 pg/mL, n.v. < 146 pg/mL) had been identified.

According to the history of illness, physical examination and initial laboratory tests strongly suggested cardiovascular system impairments. So, a series of examinations on the cardiovascular system was launched. Electrocardiography indicated abnormal left heart signalling with ST-T segment changes (lead V5–V6 ST depression > 0.05 mV, lead I, aVL depressed or inverted T waves) and prolonged QTc interval (Fig 1a). Interestingly, echocardiography demonstrated global severe heart enlargement (left ventricle = 62 mm, right ventricle = 22 mm, left atrium = 38 x 66 x 44 mm, and right atrium = 62 x 42 mm), decreased left ventricular ejection fraction (34–38%), severe multi-valve insufficiency (mitral valves, tricuspid valves, and aortic valves regurgitation), and a significant dilated aortic root (51 mm) (Fig 1b). Then the aortic CT angiography revealed multiple severe dilations of the aorta, including root, ascending, arch, and descending parts. Moreover, the most dilated segment was measured as 66.5 mm at the start of descending aorta (Fig 1d, e). Cardiac MRI presented heart enlargement and multiple aortic aneurysms. Besides, the delayed enhancement in the myocardium and subepicardial myocardial had been detected, indicating a disorder of myocardial perfusion (Fig 1c). To assess the clinical characteristics of the proband’s parents, scanning of aortic CT angiography had been applied to them, and there was no positive results according to imaging measurement.

Figure 1.

Electrocardiography and radiology manifestation in the current proband. ( a ) Electrocardiography indicated abnormal left heart signalling with ST-T segment changes and prolonged QTc interval. ( b ) Echocardiography demonstrated global severe heart enlargement and a significant dilated aortic root. ( c-c” ) Cardiac MRI presented heart enlargement and multiple aortic aneurysms. ( d – e ) The aortic CT angiography revealed multiple severe dilations of the aorta, including root, ascending, arch, and descending parts. D panel presented coronal view and E panel presented sagittal views.

After that, the potential causes for multiple aortic dilations were systematically screened. The autoimmune antibodies were negative in this patient. While rheumatic analyses were also recorded as negative, the erythrocyte sedimentation rate elevated slightly. T-spots and Xpert were involved to exclude the potential infection of tuberculosis. Furthermore, a set of viral antigens or qPCR detecting viral DNA tests had been performed, and all the results were negative. Bacterial cultures of blood and sputum also failed to address an identical infected pathogen. So, the autoimmune-associated giant vasculitis and infection-related vascular injuries had been excluded and inherited, or genetic variant-induced thoracic aortic aneurysms were suspected.

Molecular results

Based on the clinical manifestations and laboratory analyses, a genetic disorder was strongly suspected. Whole-exome sequencing was performed using the above-mentioned protocol. Based on the molecular genetic screening, a novel heterozygous variant of MFAP5 (NM_003480, c.236_237insA, p.N79Kfs*9) was found. This was a de novo variant as his parents failed to identify the same variant site (Fig 2a). While this variant was only reported in large-scale population sequencing results, which had not elucidated the association between thoracic aortic aneurysms. Although there were two records which could be retrieved from ExAC database (Fig. 2b), but this was first study to draw a link between MFAP5 c.236_237insA and thoracic aortic aneurysms. So that, we also considered this variant as a novel one in thoracic aortic aneurysms patients.

Figure 2.

The MFAP5 mutations in this family. ( a ) The proband exhibited a heterozygous variant of MFAP5 (c.236_237insA). ( b ) The variant of MFAP5 c.236_237insA has been predicted protein damaging by PolyPhen-2 and SFIT, while only two records had been retrieved of the MFAP5 c.236_237insA variant. ( c ) Protein structure predicted by AlphaFold (AF-O13361-F1). This mutation site was regulated by N-link glycosylation modification, which induced frameshift, amino acid sequence changes, protein structure changes, and slice site changes. ( d ). All the reported patients with MFAP5 variants have been presented.

Additionally, any other cardiovascular-related variants had not been retrieved between this proband and his parents. The molecular crystal structure had been built in AlphaFold (AF-Q13361-F1, Fig 2c). And this proband would be the first identified patient with heterozygous variant change on c.236_237insA of MFAP5. This mutation site was regulated by N-link glycosylation modification, which induced frameshift, amino acid sequence changes, protein structure changes, and slice site changes. According to MutationTester analysis, the variant was considered as a disease-causing mutation, and the probability value was 1.00. And PolyPhen-2 analysis demonstrated a damaging change of this protein (1.00). While the SFIT score predicted protein damaging (0.001). We have summarised all the reported variant sites of MFAP5 which was validated in thoracic aortic aneurysms. However, there were only two family with two different variants of MFAP5 had been reported before (c.62G > T, p.W21L and c.472C > T, p.R158*). Both of the reported patients with heritable thoracic aortic aneurysm were heterozygous variant carrier. The site of c.62G > T located in signal feature, while the site of c.472C > T located in chain feature. Differently, all the reported patients with MFAP5 variant-induced thoracic aortic aneurysms were limited in aortic root segment, and the age of first time on proband identified was more than 45 years old (Fig 2d). There was no other potential variant had been identified to be related with cardiovascular diseases, especially for FBN1 and FBN2 of Marfan syndrome.

Final diagnosis and treatment

Following a series of examinations and molecular tests, the child was diagnosed with heritable thoracic aortic aneurysm induced by the MFAP5 variant. Upon admission to our hospital, the patient presented with severe heart failure caused by prolonged and significant aortic valvular regurgitation. Although the patient’s parents declined artificial aortic replacement and valvar implantation, the primary therapeutic objective was to alleviate and improve the heart failure symptoms. During the hospitalisation, the patient received a combination of milrinone, dobutamine, spironolactone, furosemide, and enalapril to manage heart failure. Aspirin was administered for anticoagulation purposes, while prednisone acetate and methotrexate were prescribed for anti-inflammatory effects. Surgical correction was recommended as there are no established guidelines specifically tailored for children with heritable thoracic aortic aneurysm. Given the severity of the heart failure, the patient was initiated on Empagliflozin (10 mg daily) and Sacubitril Valsartan Sodium (100 mg twice a day) to enhance and maintain cardiac contractile function. Recently, the proband underwent thoracic aorta replacement surgery, followed by cardiac rehabilitation to improve the overall prognosis. As a result, the patient has regained the ability to engage in mild activities, and his heart function has improved to NYHA III level.