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Table of Contents
Year : 2021  |  Volume : 22  |  Issue : 3  |  Page : 214-219  

First case of tricuspid valve surgery in a neurofibromatosis type 1 patient

1 Cardiac Surgery Unit, Cardiovascular Department, H Poliambulanza Foundation, Brescia, Italy
2 Cardiac Surgery Unit, Cardiovascular Department, H Poliambulanza Foundation, Brescia; Department of Cardiovascular Surgery, University Hospital Policlinico A. Gemelli, Rome, Italy
3 Cardiac Surgery Unit; Heart Failure Surgery Unit, Cardiovascular Department, H Poliambulanza Foundation, Brescia, Italy

Date of Submission05-Feb-2021
Date of Acceptance07-Feb-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Dr. Matteo Saccocci
Poliambulanza Foundation Hospital, Via L. Bissolati 57, 25122, Brescia
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Source of Support: None, Conflict of Interest: None


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The neurofibromatosis is a large class of different genetic disorders: Neurofibromatosis type 1, type 2, type 3 (or Schwannomatosys), which have different clinical characterization. Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen disease, represents 95% of the total cases. It is a complex autosomal dominant disorder with multisystem involvement, frequently associated to cardiac malformation. We present the case of a 52-years-old male affected by NF-1 with severe tricuspid regurgitation and atrial septal defect (ASD). No previous report about tricuspid valve surgery in NF-1 are available in the literature. A complete perioperative assessment was performed, including dermatologist evaluation, angio-CT scan and trans-esophageal echocardiography. The patient underwent uneventfully tricuspid valve replacement and ASD closure, with no wound complication even at 6-months follow-up. Treating congenital malformation in patient with complex genetic disorders like NF-1 is safe and can be resolutive, permitting to reduce long-term risk of complications for the patients. Preoperative assessments are fundamental, as well as in-hospital care and expertise on congenital heart defects.

Keywords: Cardiac anomalies, cardiac surgery, neurofibromatosis, tricuspid valve, Von Recklinghausen

How to cite this article:
Saccocci M, Ferraro F, Blasi S, Del Zanna N, Villa E, Messina A, Cirillo M, Mhagna Z, Tomba MD, Troise G. First case of tricuspid valve surgery in a neurofibromatosis type 1 patient. Heart Views 2021;22:214-9

How to cite this URL:
Saccocci M, Ferraro F, Blasi S, Del Zanna N, Villa E, Messina A, Cirillo M, Mhagna Z, Tomba MD, Troise G. First case of tricuspid valve surgery in a neurofibromatosis type 1 patient. Heart Views [serial online] 2021 [cited 2023 Dec 7];22:214-9. Available from: https://www.heartviews.org/text.asp?2021/22/3/214/328019

   Introduction Top

The term neurofibromatosis identifies three different genetic disorders: Neurofibromatosis type 1, type 2, type 3 (or Schwannomatosis), which have different clinical characterization.[1]

Neurofibromatosis type 1 (NF1), also known as Von Recklinghausen's disease, represents 95% of the total cases. It is a complex autosomal dominant disorder with multisystem involvement. The NF2, rarer with a prevalence of 1 in 60,000 people, is characterized by multiple tumors of the central and peripheral nervous system (particularly the vestibular nerves, leading to deafness) and multiple meningiomas (intracranial and medullary). It is caused by a mutation of the NF2 gene located on chromosome 22. In more than 50% of cases are caused by de novo mutations. Neurofibromatosis type 3 (NF3) is the least common form and is instead characterized only by the presence of schwannomas without the involvement of the vestibular nerves.[2],[3]

Neurofibromatosis type 1 (NF1) is a neurocutaneous disease that affected about 1/3000 live births with the same prevalence between males and females [Figure 1]. The clinical presentation is extremely heterogeneous, and it is characterized by multiple café au lait spots, dermal and plexiform neurofibromas (spinal neurofibromas and peripheral nerve sheath tumors), iris LISCH nodule, intertriginous freckling (Axillary/Inguinal: Crowe's sign), choroidal freckling, learning disabilities, and attention deficits. Other manifestations can include skeletal abnormalities, brain tumors, pheochromocytoma, and cardiovascular disease, including vasculopathy (vascular stenosis, occlusion, aneurysm, rupture, and fistula formation), hypertension, congenital heart defects, and hypertrophic cardiomyopathy.[4],[5]
Figure 1: Orphanet definition

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NF1 is caused by heterozygous mutation of the NF1 gene, located on chromosome 17q11.2, that codes for a protein belonging to the GTPase-activating protein family with tumor suppressor function: Neurofibromin. In 90%–95% of cases, the disease is caused by an intragenic mutation (frameshift, nonsense, splice site mutation, and copy number variation) while the remaining 5%–10% by long deletions (whole-gene deletion WDG).[6] De novo mutations of the NF-1 gene represent about 50% of the cases, explaining the presence of patients with a familiar negative history.

Penetrance typically reaches 100%, although an extreme variation in clinical presentation.

The definitive diagnosis is usually obtained around 4 years of age,[7] and it is primarily clinical, being made in the presence of two or more diagnostic criteria [Table 1]. Genetic analysis is usually not needed.
Table 1: Diagnostic Criteria for neurofibromatosis type 1 by the National Institutes of Health (1988)

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The overall prognosis is good; nevertheless, NF1 patients have a lower life expectancy than the general population, with an estimated reduction from 8 to 21 years. Tumors and cardiovascular diseases are the most common causes of early death.

In fact, the neurofibromin-coding gene has an essential role in the control of apoptosis, cellular proliferation, and cellular differentiation, and it is expressed ubiquitously in several cell lines, including neurons, glial cell, immune cells, endothelial cell, smooth muscle cell, and in cells of the adrenal medulla. In particular, neurofibromin plays an important role in the development of the cardiovascular system, as reported by several studies that show a significant interaction between blood cells and endothelial cells and the smooth muscle of the vessel.[8] Large and small vessels can be involved in type 1 neurofibromatosis. The most frequent anomalies can be seen in renal arteries, abdominal aorta (coarctation), and in the cerebrovascular district (stenosis or occlusion of the internal carotid artery, middle and anterior cerebral artery; small peri-stenotic telangiectasias with characteristic angiographic aspect known as "puff of smoke" (moyamoya).[9]

In the literature, the incidence of congenital heart defects in NF1 patients varies from 0.4%–6.4%. According to the demonstrated important role of neurofibromin in cardiac organogenesis, an increased incidence of heart defects is reported in many studies about NF-1. The most frequent pathologies described are mitral valve anomalies, interatrial septal abnormalities (ostium secundum and septal aneurysm), pulmonary valve stenosis, cardiomyopathy, and aortic valve insufficiency.[3],[6],[10]

To the extent of our knowledge, this the first report of a patient affected by NF1 disease undergoing cardiac surgery for the treatment of tricuspid valve insufficiency and atrial septal defect (ASD).

   Clinical Presentation Top

A 52-year-old male affected by neurofibromatosis-1 was referred to our center for evaluation and treatment of worsening of tricuspid valve regurgitation already known since his childhood. Before the age of two years old, he started presenting multiple diffuse cutaneous neoformations [Figure 2]. Clinical evaluation posed a diagnosis for diffuse neurofibromatosis (Recklinghausen disease). No previous case had been reported in his family. During medical investigations, a systolic murmur was reported as a sign of tricuspid insufficiency.
Figure 2: Plexiform cutaneous neurofibromas

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At the age of 15 years old, to exclude an Ebstein disease, he underwent right cardiac catheterization with no reported evidence of congenital pathology. The patient performed regular medical follow-up and had a normal physical and mental development. In the past years, he started complaining worsening of exertional dyspnea (NYHA II) during work activity. The cardiologist visit confirmed tricuspid insufficiency murmur and required further medical investigations.

The last transthoracic echocardiography (TTE) showed severe tricuspid regurgitation (TR) with right chambers overload, pulmonary hypertension (PAPS 49 mmHg). Electrocardiography (EKG) was characterized by a stable sinus rhythm with right branch block.

Pneumologist evaluation concluded for a chronic latent respiratory insufficiency documented by chronic respiratory alkalosis at arterial blood gas test (ABG) despite a normal spirometry test. Due to the exacerbation of the symptoms, he finally underwent cardiac surgery consult. The indication for surgery was clear, as reported in EACTS and AHA guidelines (guidelines).

Given the already known respiratory insufficiency, we decided for a traditional median sternotomy approach. As suggested during the preoperative assessment, to avoid cutaneous lesions during the skin incision, the dermatologist evaluated the patient to remove the neurofibromas presented above the sternum region. On admission, the patient presented exertional dyspnea (NYHA III) with no other cardiac symptoms.

A standard preoperative TTE confirmed massive TR with annular dilatation, right ventricle enlargement with preserved motility, normal left ventricle function, and motion, floppy atrial septum, and paradoxical movement of the interventricular septum [Figure 3]. The echocardiographic assessments were completed by transesophageal echography (TEE): Complete loss of coaptation of the tricuspid leaflets, right chambers dilatation, no clear evidence of left to right shunt, but a suggestive image for ostium secundum defect was present.
Figure 3: Preoperative (a, b) and postoperative (c, d, e) echocardiographic imaging.

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To exclude congenital cardiac malformations, the patient underwent an angio-computed tomography (CT) scan [Figure 4]: no anomalous venous return, no anatomical variations, normal thoracic aorta, and pulmonary artery diameters. Coronary angiography showed no evidence of significant stenosis.
Figure 4: Preoperative cardiac computed tomography scan (a - b: 3D CT scan reconstruction, c, d, e, f: cross sectional views of atrial septal defect and tricuspid valve)

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ABG test presented hypoxemia (pO2 55 mmHg), hypocapnia (pCO2 30 mmHg), low-oxygen hemoglobin saturation (O2Hb 89.1%), and pH 7.44.

Based on these findings, the patient was scheduled for surgical intervention for tricuspid valve replacement (TVR), atrial septum defect (ASD) correction, and epicardial leads implantation as planned for all tricuspid valve replacement performed in our center.

On the surgical day, intraoperative TEE confirmed massive the severe TR and the ostium secundum septal defect. Through a complete median sternotomy, we performed central cannulation (bicaval venous drainage). After cardiopulmonary bypass (CPB) implantation, retrograde cold blood cardioplegia (Buckberg protocol) was administered in the coronary sinus. The incision of the right atrium was performed, as usual, permitting a complete visualization of the ASD (elliptical shape and 2 cm maximum diameter) and the tricuspid valve. There was no possibility of valve reparation, as expected, due to extreme tricuspid annulus dilatation associated with abnormal atrophic septal leaflet. We decided for a 31 mm bioprosthesis (BioIntegral Surgical, Mississauga, Canada) implanted with everting single stitches (2/0 Premicron with Teflon pledgets) [Figure 5] and a direct suture of the ASD.
Figure 5: Tricuspid valve replacement with biomitral valve (Biointegral Surgical Inc.) and epicardial lead implantation. (a: tricuspid valve preparation; b: epicardial lead implantation; c: atrial septum defect; d - e: biomitral valve prosthesis)

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After the atriotomy closure, we proceed with anterograde reperfusion that granted a spontaneous sinus rhythm restoration before cross-clamp removal. Nevertheless, in the absence of any cardio-electrical alterations, we decided to implant an epicardial electrode on the right ventricle wall to preserve the bioprosthesis in case of further need of ventricular pacing.

The postoperative course was uneventful, with an endotracheal intubation time inferior to 6 hours, no need of inotropes drugs, and total postoperative in-hospitable stay of 5 days. No EKG alteration was present at discharge, and echocardiographic evaluation showed preserved left and right ventricle contractility, no evidence of intracardiac shunt, and normal bioprosthesis function (mean trans-prosthesis gradient 7 mmHg). The 6 months follow-up has been uneventful with a complete return to normal life, no symptoms, and no sternal wound infection or abnormalities.

   Discussion Top

As reported in the literature,[6],[3],[10],[11] congenital heart defects are common in patients affected by Von Recklinghausen's disease. Some of them can be successfully treated with surgical correction, as demonstrated by this case. No reported tricuspid valve treatments in NF-1 patients have been reported in the literature. Accurate preoperative assessment is crucial;[12] many patients have multiple cardiac anomalies that can be associated with vascular pathologies of other districts. To exclude cerebral aneurysms, adding head acquisitions to the standard chest angio-CT scan is always suggested.

Routinely preoperative blood tests and pulmonary function tests are compulsory as well as a TEE in case of surgery indication. Tricuspid valve insufficiency is usually routinely repaired in a high percentage of patients in our center and all high-volume centers. The decision to replace the valve with a bioprosthesis was obliged by the significative leaflet alterations associated with extreme annulus dilatation.

The optimal valve substitute in the tricuspid position is still debated. The latest studies published seem to agree that mid- and long-term follow-up of biological and mechanical prostheses do not differ in patients undergoing TVR.[13],[14] This is confirmed by a large metanalysis that analyzed more than 2600 patients,[15] where was observed a higher risk of thrombosis in the case of mechanical TVR. This seems to endorse our philosophy of choosing a bioprosthetic valve in most of our TVR cases.

Since the past couple of years, we have good intraoperative and postoperative results using in tricuspid position the BioMitral valve (Biointegral Surgical Inc., ON L4Z 1S6, Canada) a complete pericardial valve based on a porcine valve. Its smoothness is perfect for tricuspid annulus conformation. Besides, in a recent publication about TVR by Wiedemann et al., porcine tricuspid prosthesis seems to have some advantages compared to bovine ones, due to the lower closing volume needed. The presence of an endoventricular electrode could be harmful to the correct function of the tricuspid valve. For this reason, in most of cardiac right-side surgery, to preserve the prosthetic or repaired valve, we used to place an epicardial electrode on the right ventricle, ready to be connected to a subclavian PM generator in case of future need. The interatrial defect, very common in NF-1 patients, was simply corrected with a direct suture thanks to its narrow dimension. No sternal wound infections occurred during the hospitalization; normal healing was observed at a distance of 6 months without any sequelae.

   Conclusions Top

Cardiac surgery in NF-1 is feasible and can be restorative, permitting to reduce long-term risk of complications for the patients. Preoperative assessments are fundamental, as well as in-hospital care and expertise on congenital heart defects.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Orphanet the Portal for Rare Diseases and Orphan Drugs. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Expert=636&lng=EN. [Last accessed on 2021 Mar 08].  Back to cited text no. 1
Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol 2005;141:71-4.  Back to cited text no. 2
İncecik F, Hergüner ÖM, Alınç Erdem S, Altunbaşak Ş. Neurofibromatosis type 1 and cardiac manifestations. Turk Kardiyol Dern Ars 2015;43:714-6.  Back to cited text no. 3
Uusitalo E, Leppavirta J, Koffert A, Suominen S, Vahtera J, Vahlberg T, et al. Incidence and mortality of neurofibromatosis: A total population study in Finland. J Invest Dermatol 2015;135:904-6.  Back to cited text no. 4
Gutmann DH, Ferner RE, Listernick RH, Korf BR, Wolters PL, Johnson KJ. Neurofibromatosis type 1. Nat Rev Dis Primers 2017;3:17004.  Back to cited text no. 5
Pinna V, Daniele P, Calcagni G, Mariniello L, Criscione R, Giardina C, et al. Prevalence, type, and molecular spectrum of NF1 mutations in patients with neurofibromatosis type 1 and congenital heart disease. Genes (Basel) 2019;10:675.  Back to cited text no. 6
Friedman JM. Neurofibromatosis 1. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993.  Back to cited text no. 7
Lasater EA, Li F, Bessler WK, Estes ML, Vemula S, Hingtgen CM, et al. Genetic and cellular evidence of vascular inflammation in neurofibromin-deficient mice and humans. J Clin Invest 2010;120:859-70.  Back to cited text no. 8
Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, et al. Cardiovascular disease in neurofibromatosis 1: Report of the NF1 Cardiovascular Task Force. Genet Med 2002;4:105-11.  Back to cited text no. 9
Tedesco MA, Di Salvo G, Natale F, Pergola V, Calabrese E, Grassia C, et al. The heart in neurofibromatosis type 1: An echocardiographic study. Am Heart J 2002;143:883-8.  Back to cited text no. 10
Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, et al. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet 2000;95:108-17.  Back to cited text no. 11
Fox CJ, Tomajian S, Kaye AJ, Russo S, Abadie JV, Kaye AD. Perioperative management of neurofibromatosis type 1. Ochsner J 2012;12:111-21.  Back to cited text no. 12
Redondo Palacios A, López Menéndez J, Miguelena Hycka J, Martin Garcia M, Varela Barca L, Ferreiro Marzal A, et al. Which type of valve should we use in tricuspid position? Long-term comparison between mechanical and biological valves. J Cardiovasc Surg (Torino) 2017;58:739-46.  Back to cited text no. 13
Liang W, Yue H, Li T, Qin X, Qian Y, Wu Z. The better substitute for tricuspid valve replacement in patients with severe isolated tricuspid regurgitation. Anatol J Cardiol 2019;22:172-6.  Back to cited text no. 14
Liu P, Qiao WH, Sun FQ, Ruan XL, Al Shirbini M, Hu D, et al. Should a mechanical or biological prosthesis be used for a tricuspid valve replacement? A meta-analysis. J Card Surg 2016;31:294-302.  Back to cited text no. 15


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]

  [Table 1]


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