Introduction
Cutis laxa is a rare autosomal recessive disorder characterized by abnormal elasticity in the organs that embryologically derive from the mesoderm. Histopathological findings are characterized by widespread disruption of elastic fibers. It develops due to a homozygous or heterozygous mutation at the FLBN4 (EFMP2) gene locus on chromosome 11q13. Aortic root aneurysm is perhaps the most lethal associated condition.
Pediatric cases of aortic root aneurysm, although rare, may present significant risks if not managed in a timely manner. Careful monitoring is therefore required, and timely surgical intervention should be considered when clinical features warrant. Reference Krishnan Nair, Pillai and Mathew1,Reference Sülü, Başpınar and Şahi2
Case presentation
A 12-year-old male was referred from another centre with a history of non-specific chest pain of 2 months’ duration. He was thought to have cutis laxa syndrome, based on clinical criteria. There was no relevant family history. Physical examination showed typical cutaneous features of cutis laxa, including a broad forehead, blepharochalasis, large earlobes, an increased nasolabial fold, and drooping cheeks and jowls. Vital signs were as follows: weight, 66 kg; height, 155 cm; hemoglobin oxygen saturation, 100%; heart rate, 80/min; and blood pressure, 154/78 mmHg. The cardiovascular exam was further remarkable for a suprasternal thrill and a grade 3/4 systolic-diastolic murmur at the upper right sternal border. Imaging studies, including 2D echocardiography (Figure 1) and computed tomographic angiography (Figure 2), revealed a significantly dilated ascending aorta (7.0 cm, Z-score = 12.4) consistent with aortic root aneurysm. There was severe aortic valve regurgitation as well. Genetic assessment, including genotyping, identified two pathogenic variants in EFEMP2—c. 409A>T (p. Ser137Cys) and c.1135del (p. rg379Valfs × 27)—confirming the diagnosis of cutis laxa syndrome.
( a ) 2D echocardiographic long-axis view demonstrating aortic annulus dilation and ascending aortic aneurysm. ( b ) Colour Doppler interrogation showing severe aortic valve regurgitation.
CT angiogram demonstrating in ( a ) anterior view of aneurysmal dilation of the proximal segment of the ascending aorta. ( b ) Shows the posterior view with marked displacement of the right heart and distal ascending aorta.
Management was started with atenolol. He presented 12 weeks later with a 15-day history of fever and was therefore hospitalised. An echocardiogram at that time showed a moderate anterior and posterior pericardial effusion. He received 3 weeks of intravenous antibiotics for a presumed diagnosis of septic pericarditis. CT angiography was repeated, confirming the diagnosis of ascending aorta aneurysm, which had not progressed since the first study. The maximal ascending aortic diameter was again 7.0 cm (Z-score = 12.4), and the aortic annulus was 2.6 cm (Z-score = 3.4). Cerebral, abdominal, and pelvic CT angiography were normal, except for a small quadrigeminal cisternal lipoma.
Surgical procedure
Given the size of the aneurysm, the aortic insufficiency, and the patient’s underlying connective tissue disorder, a Bentall procedure was chosen as primary treatment. Following median sternotomy, the pericardium was found to be thick and adherent to the aorta. There was a huge aortic root aneurysm extending to the innominate artery (Figure 3). The distal ascending aorta and transverse arch were of normal calibre. Cardiopulmonary bypass (CPB) was established between a femoral artery, left atrial appendage, and left pulmonary artery because the right atrium and caval veins were compressed and displaced posteriorly by the aneurysm and were not visible in the field. The femoral veins were diminutive. The temperature was lowered to 28°C, and the aorta was cross-clamped and opened. Direct ostial cardioplegia was administered, and the non-coapting aortic leaflets were excised. After opening the aorta over the full length of the aneurysm, coronary arterial buttons were excised. The aneurysmal portion of the ascending aorta was excised down to the annulus. A composite 23 mm On-X valve bearing Dacron tube graft was sutured to the annulus, and the distal end was anastomosed to the distal ascending aorta. Coronary buttons were implanted into the graft sinuses. After declamping, defibrillation, and full warming, the operation was completed without incident. Cardiopulmonary bypass time was 4 hours 38 min, and ischaemic time was 2 hours 34 min.
( a ) Open chest showing adhesions and a large aneurysm. ( b ) Arrow showing venous cannula in the left atrium. ( c ) Aneurysm wall open, resection in progress.
Outcome
The patient’s postoperative course was uneventful, and he was discharged 10 days after surgery, receiving atenolol, losartan, warfarin, and furosemide. One week after discharge, the patient was re-admitted due to a painful mass in the right inguinal area. An echo-Doppler study suggested the presence of a pseudoaneurysm of the right femoral artery (at the cannulation site). However, at surgical exploration, a simple hematoma was found and evacuated without event. The patient was discharged after a 4-day stay.
At 3 months postoperative follow-up, the patient was asymptomatic, but a routine 2D echocardiogram suggested a large mediastinal fluid-filled mass compressing the right atrium. CT angiogram showed a large, partially thrombosed peri-prosthetic pseudoaneurysm of the ascending aorta, measuring approximately 14.8 × 12.6 cm and extending from the sinus of Valsalva to the transverse arch (Figure 4). The pseudo-aneurysmal mass was heterogeneous, with spontaneously hyperdense areas observed in the simple phase. In the contrast phase, different densities were noted within the thrombus, suggesting a hematoma in multiple stages of evolution (sub-acute, acute, and chronic). There appeared to be a flow into and out of the aneurysm across a small area of conduit distal anastomotic disruption. We performed cardiac catheterization to assess suitability for interventional treatment.
( a ) Axial image of the thorax showing the pseudoaneurysm. ( b ) Sagittal view. The arrows show the extension of the pseudoaneurysm in the thorax.
Under general anesthesia, using a 5 Fr pigtail catheter in a retrograde course, an angiogram was done in antero–posterior and lateral views. In the ascending aorta, a 5 mm leak into the pseudoaneurysm was evident at the junction of the conduit and the native aorta. A 0.035 hydrophilic guide wire and a 4 Fr JR catheter were used to cross the defect. With a 0.035 super stiff wire and a 6 Fr TorqVue 45× delivery system, an Amplatzer 6 mm septal occluder was delivered, with the first disk within the hematoma collection (towards the wall of the aorta) and the second disk on the inner wall of the ascending aorta at its junction with the conduit. No residual shunt nor vascular obstruction of any aortic branch was observed immediately after placement (Figure 5).
( a ) Anterior–posterior angiogram showing 6 mm defect with a shunt from the ascending aorta to the pseudoaneurysm. The blue arrow marks the neck of the pseudoaneurysm. ( b ) Lateral angiogram showing defect closed with Amplatzer 6 mm septal occluder. The white arrow marks the device.
An echocardiogram 2 months after the catheter procedure showed a decrease in the size of the aneurysm. The hyperechoic image anterior to the heart measured 12.3 × 9.5 cm. The patient remained well, and we await further resolution of the hematoma, which we expect will take months (based on experience with related adult cases). We monitor the pseudoaneurysm closely with an echocardiogram every 3 months and a CT angiogram once a year. Surgery will be considered if the patient develops symptoms indicating right-sided heart compression, if there is an increase in the size of the pseudoaneurysm, or if an infection is detected.
Discussion
Cutis laxa has a prevalence of approximately 1 in 400,000 individuals and is characterized by defects in elastic fibers, resulting in loose, wrinkled skin. In 1855, Alibert used the term « cutis laxa » to describe patients with “redundant skin.” Goltz described the characteristic histopathology in 1965, and Brigthon proposed the genetic classification of cutis laxa in 1972.
There are two main types of cutis laxa: acquired and congenital. Congenital forms can be X-linked recessive, autosomal dominant, or autosomal recessive. Acquired forms of cutis laxa include those associated with aging, which increases skin laxity (a process normally accelerated by photodegeneration), and with other conditions, such as the state following severe edema and large weight losses in morbidly obese individuals. In congenital cutis laxa, point mutations are now known to occur, including anomalies of microfibrillar proteins fibulin 4 and 5. These may be present in both the dominant and recessive forms, indicating the genetic heterogeneity. A mutation of ATP6V0A2 that encodes subunit 2 of the ATPase-V-type H+, which is found in the recessive form, results in abnormal glycosylation. A mutation of the elastin gene on chromosome 7q11 is presumed to affect only the autosomal dominant form. Reference Morales, Ramírez Carlos and Mena3
The main associated cardiovascular abnormalities in cutis laxa are ventricular septal defect, aortic (and other vascular) aneurysms, carotid tortuosity, and stenosis of the pulmonary artery branches. Reference Morales, Ramírez Carlos and Mena3
Aortic root aneurysm in pediatric patients is extremely rare, with most cases documented in association with genetic systemic connective tissue disorders (including Marfan, Loeys-Dietz, Ehlers-Danlos, cutis laxa, and others). Many pediatric root aneurysm cases cannot be effectively treated with valve-sparing root reconstruction (the procedure of choice for suitable candidates). The Bentall procedure is an excellent choice for such cases, and it has withstood the test of time with good long-term outcomes in a variety of pathologic settings in all ages. Reference Krishnan Nair, Pillai and Mathew1
The Bentall procedure can present complications such as pseudoaneurysm, and in patients with connective tissue disorders, this complication is more likely to occur. Potential causes include excessive suture line tension, graft infection, application of vascular glue, anticoagulation, and primary blood collections in the paraaortic space. Postoperative pseudoaneurysms typically develop at aortotomy and cannulation sites, needle punctures, cross-clamping lines, and vascular anastomoses. As well summarised by Saul et al., “The development of aortic pseudoaneurysm after the Bentall procedure remains a potential complication both in the early and late follow-up periods, with incidence reported in historical publications of up to 7–25% of graft replacements.” Reference Saul, Kandula and Donuru4 We believe that reinforcing the suture line between the graft and the native ascending aorta with a Dacron strip around the aortic circumference could have prevented the leak in the suture line. Given that cutis laxa is a connective tissue disorder, this approach would represent a safer surgical technique.
In recent years, advances in artificial intelligence have resulted in new diagnostic and surgical planning strategies that make less invasive management of aortic root aneurysm patients possible, especially in cases with postoperative complications. This concept and its ramifications have been discussed recently in a report from Poland by Galeczka et al. Reference Galeczka, Anel and Dyrbus5
Although we did succeed in our interventional rescue approach, we suggest that at present, ascending aorta endovascular repair should be reserved for high surgical risk patients with lesions limited to the sinotubular junction or to the tubular portion of the ascending aorta. Also, in our case, we recognize that further resolution of the large pseudoaneurysm space is not certain, and the time scale remains speculative. Infection in this space, leading to mediastinitis, remains a possibility. With this in mind, and given the risks of further open surgery, we are currently following the patient monthly as we await resolution. Reference Di Marco, Lovato and Murana6
Conclusion
This report underscores the importance of comprehensive cardiovascular monitoring and the potential benefits of early surgical intervention for aortic root aneurysm in pediatric patients with cutis laxa. The successful application of the Bentall procedure in this case raises the possibility of favorable outcomes for similar patients, advocating for its consideration in future cases of pediatric aneurysms associated with connective tissue disorders.
Acknowledgements
We acknowledge the clinical contribution of Dr John Breinholt to the care of this patient.
Financial support
Nil.
Competing interests
The authors declare none.
Ethical standard
The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national guidelines on human experimentation (APA) and with the Helsinki Declaration of 1975, as revised in 2008, and have been approved by the CEDIMAT institutional committee.
