REVIEW ARTICLE
Pediatric Vascularized Composite Allotransplantation Gaby Doumit, MD, MSc, Bahar Bassiri Gharb, MD, PhD, Antonio Rampazzo, MD, PhD, Francis Papay, MD, Maria Z. Siemionow, MD, PhD, DSc, and James E. Zins, MD Background: Vascularized composite allotransplantation (VCA) has experienced a growing acceptance, which has led to a debate centered on extending the indications of the procedure to include pediatric patients. The aim of this article was to discuss such indications based on the evidence in pediatric solid organ transplantation, reconstructive surgery in children, and VCA in adult patients. Methods: Papers published on the outcomes of pediatric solid organ transplantation, growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, facial fractures, and outcomes after repair of peripheral nerves in children were reviewed. Results: Although the outcomes of solid organ transplantation in children have improved, the transplanted organs continue to have a limited lifespan. Long-term immunosuppressive therapy exposes the patients to an increased lifetime risk of infections, diabetes, hypertension, dyslipidemia, cardiovascular disease, and malignancy. Growth impairment and learning disabilities are other relevant drawbacks, which affect the pediatric recipients. Nonadherence to medication is a common cause of graft dysfunction and loss among the adolescent transplant recipients. Rejection episodes, hospitalizations, and medication adverse effects contribute negatively to the quality of life of the patients. Although normal growth after limb transplantation could be expected, pediatric facial transplant recipients may present with arrest of growth of transplanted midfacial skeleton. Conclusions: Considering the nonYlife-threatening nature of the conditions that lead to eligibility for VCA, it is suggested that it is premature to extend the indications of VCA to include pediatric patients under the currently available immunosuppressive protocols. Key Words: pediatric vascularized composite allotransplantation, vascularized composite allotransplantation, VCA, face transplantation, hand transplantation, microsurgery, reconstructive surgery, children (Ann Plast Surg 2014;73: 445Y450)
W
ith more than 150 vascularized composite allotransplants performed worldwide, many of the technical, logistic, and ethical aspects of the procedure have been addressed. Acceptable graft survival and functional outcomes have been achieved under the current immunosuppressive regimens, creating the ground for a gradual extension of the indications for vascularized composite allotransplantation (VCA). Although allotransplantation of nonvital organs is a controversial issue, pediatric VCA is an even greater subject of debate. Boston Children’s Hospital recently announced the establishment of the first pediatric hand transplantation program in the world.1 Patients between 10 and 25 years of age who had lost both hands, or who missed only 1 hand but either were already on immunosuppressive medication for a solid organ transplant or had a poorly
Received February 9, 2014, and accepted for publication, after revision, June 5, 2014. From the Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH. Conflicts of interest and sources of funding: The authors have no conflict of interests to disclose. This project was supported by institutional funds. Reprints: Gaby Doumit, MD, MSc, Dermatology and Plastic Surgery Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7304-0445 DOI: 10.1097/SAP.0000000000000300
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functioning contralateral hand were being considered eligible for hand transplantation.2 Of note, as one of the institutions with institutional review board approval for face transplantation, our center has also been receiving referrals for pediatric face transplantation (Fig. 1). The evidence derived from pediatric solid organ transplantation proves that children pose unique challenges, which transcend the technical and immunological feasibility issues. Ideally, in the event of transplantation, the composite allograft should preserve the potential to grow with the recipient to achieve optimal restoration of function and form and to avoid multiple secondary procedures. In the present study, the current evidence on the outcomes of solid organ transplantation in children is summarized and the possible deleterious effects of the allotransplantation in pediatric recipients are elucidated. The potential for growth of the composite allografts after transfer is examined and the lessons learned from the global experience with VCA in adults are discussed with special regard to aspects relevant to pediatric patients.
MATERIALS AND METHODS Search Strategy and Selection Criteria Comprehensive MEDLINE search was performed in the English literature for peer-reviewed articles, published between 2005 and 2013, on the state of art of solid organ transplantation in pediatric patients. A second MEDLINE search was performed to retrieve papers on the growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, and facial fractures in pediatric patients. Finally, we searched for papers detailing the outcomes after repair of peripheral nerves in children. The keywords used in the search are summarized in Table 1.
RESULTS Pediatric Organ Transplantation General Outcomes Five- and 10-year allograft survival rates have dramatically improved during the last several years3 (Table 2). With both longer allograft and patient survival, adverse outcomes have been increasingly witnessed (Table 3). Among pediatric recipients of solid organ transplants, the cardiovascular disease risk factors are exponentially increased with the ensuing cardiovascular morbidities threatening both graft and patient survival4,5 (Table 3).6 Hypertension usually occurs within the first year after transplantation and persists into adulthood.7 Older than 12 years at the time of transplantation, presence of intact native kidneys, at least 1 episode of acute rejection, and cadaveric allograft all correlate with an increased risk of developing hypertension after transplantation.8 Dyslipidemia is another significant contributor to cardiovascular disease in children. The prevalence is increased in the first year affecting between 26% and 56% of pediatric solid organ recipients.9 Posttransplantation diabetes affects between 2.6% and 17% of pediatric transplant patients7 and the incidence increases with time after transplantation.10 The incidence of renal dysfunction in nonrenal transplants has been reported between 24% and 70%.11,12 www.annalsplasticsurgery.com
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Steroids are associated with significant dose-dependent and cumulative toxicity.17 In particular, children who receive chronic steroids are more prone to growth retardation despite minimizing cumulative dosing.
Infectious Disease Age is an important determinant of susceptibility to infection and disease severity.18 Infections are the most common cause of death (28.6%) and hospitalization19 among pediatric renal transplant recipients.3 Often young children lack immunity to many pathogens before transplantation and are at higher risk of acquiring primary infection with many organisms after they are immunosuppressed, leading to increased morbidity.20,21 Both Epstein-Barr virus (EBV) and cytomegalovirus have been associated with indirect immunomodulatory effects leading to an enhanced susceptibility to other opportunistic infections, PTLD, as well as an increased risk of graft rejection.22 Primary EBV infection is the most clearly defined risk factor for the development of early PTLD, and children are at considerably higher risk of developing PTLD than adults as they are often EBV naive at the time of transplantation.21
Malignancy
FIGURE 1. A 15-year-old adolescent girl was referred to our department for an opinion regarding face transplantation. In 2008, she was diagnosed with fibrous dysplasia and had undergone 9 debulking procedures in other major academic centers during the past 4 years. The mass obliterated the nose and extended 9 cm anterior to the facial plane. Her nostril opening measured 4 5 cm bilaterally. Her bilateral orbits were displaced laterally and superiorly resulting in hypertelorism, dystopia, and proptosis. Her maxilla, zygoma, and maxillary alveolus were also severely deformed. Her vision and facial nerve function were intact. As the institutional review board protocol for face transplant at our institution is presently not approved for patients younger than 18 years, a decision was made for surgical resection of the tumor and temporary reconstruction with titanium mesh plates given the aggressive nature of the disease. At 1-year follow-up, there was no evidence of recurrence. The patient was quite satisfied with her appearance. Intranasal examination demonstrated mucosalization of the titanium mesh.
Immunosuppressive Treatment Current immunosuppression protocols typically involve 4 agents, namely, an induction agent, corticosteroids, an antimetabolite (mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine, tacrolimus).13 The efficacy of these regimens is demonstrated by the low retransplantation rates for chronic rejection, which vary between 5% and 25% for all organ types.6 Interleukine-2 antagonists (basiliximab and daclizumab) remain the preferred induction agents in children given the higher risk of posttransplant lymphoproliferative disease (PTLD) and cytomegalovirus disease seen with T-cellYdepleting agents (antithymoglobulin and OK3). Calcineurin inhibitors are the main risk factors for posttransplant hypertension, with an increased risk when steroids are coadministered.14 Cyclosporine and tacrolimus can lead both to acute and chronic nephrotoxicity.15,16 446
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Children remain one of the most vulnerable populations for developing cancer posttransplantation, especially because of immune naivety and longer exposure to immunosuppression.23 The incidence of cancer among pediatric transplant recipients is as high as 10 times the incidence for the nontransplanted same age group.24 The incidence of nonskin malignancy after 10 years of chronic immunosuppression in all solid organ recipients has been estimated at 20%, with a greater than 40% incidence after 20 years.25 Currently, malignancies are the second most common cause of transplant recipients’ mortality.23 Among pediatric solid organ transplant recipients, PTLD remains the most common neoplasm (50%).23,25 The risk of PTLD is 3.7-fold higher in the pediatric transplant population with an incidence of 2.2% compared to 0.4% in adults.26 Skin cancers, especially squamous and basal cell carcinomas are the second most common malignancies (26%) in the pediatric population (Table 4).25,27
Growth and Orthopedic Complications Normal development can be delayed in pediatric recipients of solid organs, with deficiencies encountered both in physical stature as well as cognitive and psychosocial functions. Younger age at the time of transplantation, graft dysfunction, acute rejection, and use of corticosteroids are some of the risk factors for growth impairment.28 Transplantation and immunosuppressive medications increase the risk of fractures and avascular necrosis, delay the growth and cause TABLE 1. Keywords Used for Literature Search Solid organ transplantation in children Pediatric solid organ transplantation Free flaps in children Free tissue transfer in children Free fibula in children Toe to hand transfer Replantation in children Growth after orthognathic surgery Growth after facial fractures Growth after Le Fort Outcomes nerve repair in children
and Outcomes and Outcomes or Pediatric or Pediatric or Pediatric and Growth and Growth
or Pediatric
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TABLE 2. Long-term Adverse Outcomes in Pediatric Solid Organ Allotransplantation Organ
5-y Survival, %
10-y Survival, %
Liver Kidney Heart
68Y75 68Y84 68Y75
80Y85 80 60Y80
In kidney transplant recipients, it is not possible to differentiate long-term nephrotoxicity from chronic rejection.
pathologic development of the spine.29 Compared with age-matched controls, the incidence of fractures in allograft recipients is 6-fold higher.30
Cognitive Development and Psychiatric Issues Current studies support that neurocognitive delay is an important problem in children receiving organ transplants; however, this could be related to the severity of chronic organ failure pretransplantation.31 Both liver and kidney transplant survivors are in the low interquartile range compared to their peers and complain of memory lapses and poor concentration.32 Various psychological outcomes such as depression, anxiety, and even frank psychiatric disorders have been reported to occur frequently among pediatric transplant recipients.33 The need for independence, typical of the adolescence, coupled with a notion of invulnerability often leads to nonadherence34 to medications. This has been reported ranging between 15% and 22%34 and is the major cause of graft loss or rejection in adolescent transplant recipients.35
Quality of Life Solid organ transplant recipients usually have improved quality of life (QoL) compared to pretransplant period and lower QoL compared to healthy peers.36 Prevailing concerns affecting QoL after transplantation are physical symptoms, body image, school disruption, and strained family/peer relationships. Rejection episodes, hospitalizations, and medication adverse effects all contribute negatively to QoL.3 Zamora37 reported that the majority of young adults with childhood renal transplants lived with their parents, had no type of sexual relationship, and perceived their future as limited and remained anxious about possible organ rejection, despite being in good health.
University of Pittsburgh reported that operational tolerance after pediatric liver transplantation was achieved in nearly 20% of selected patient populations. Despite 29% of the patients developing proven rejection, none of the patients lost the allograft.39 University of Kyoto40 achieved a 15% complete withdrawal of immunosuppression in their cohort of 581 pediatric liver transplant recipients. Noteworthy, tolerant patients, despite normal liver function, exhibited a decrease in size and an increase in number of bile ducts, as well as a higher degree of fibrosis. These findings reveal that the risk of chronic rejection could be significantly higher in these patients in the long run.41
Growth Potential After Reconstructive Procedures in Children Continued skeletal growth is usually observed in the amputated parts after replantation if the growth plates are not injured.42Y45 Growth rates in digital replantation have been reported being more favorable than those in major limb replantation: 88% to 100% and 75% to 96% of the noninjured side, respectively.45 Chang and Jones46 showed preserved growth potential in pediatric toe to hand transfer with equal length of the transferred and contralateral toe. The duration of ischemia has been shown to affect adversely the growth after replantation, with normal bone growth attained when ischemia time did not exceed 3 hours.45 Recovery of sensation has been reported to occur faster than in adults, with near normal 2-point discrimination and light touch in pediatric digital replantation and vascularized toe to hand transfer.47,48 Chemnitz et al49 compared the functional outcome after complete injuries to median and ulnar nerves in childhood (G12 years) and adolescence (12Y20 years), showing superior sensory and motor recovery in childhood injuries. Similar results were reported by Duteille et al,50 who studied 38 median and ulnar nerve injuries at wrist level, confirming a markedly superior sensory recovery in children. Fasciocutaneous free f laps retain the growth characteristics of the donor site, including hair and bulk.51 No obvious difference in the growth rate between fasciocutaneous f laps, muscle f laps with split-thickness skin graft, and myocutaneous flaps has been demonstrated.52 The children display an increased tendency toward hypertrophic scarring53 and a high rate of secondary procedures are necessary to correct the scar contracture developing along the margins of the f lap (16%Y39%).54Y56 Vascularized bone transfer, for reconstruction of mandibular or extremity defects, has shown that the preservation of the epiphyseal growth plate is necessary to allow continued growth TABLE 4. Malignancies in Pediatric Organ Transplant Recipients
Tolerance Many of the protocols to induce tolerance have not included pediatric transplant candidates.38 In one of the few pediatric trials, the TABLE 3. Long-term Allograft Survival in Pediatric Solid Organ Transplantation Hypertension Dyslipidemia Diabetes Nephrotoxicity PTLD Malignancy Retransplantation rate
Pediatric VCA
Liver, %
Kidney, %
Heart, %
28 26 5 5 5Y7 12 5Y10
70 56 2.6 NA 7 17 25
35 40 17 4 17 1Y4 5
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Type of Tumor
Percent of Total Tumors Reported
PTLD Nonmelanoma skin cancer Gynecologic Kaposi sarcoma Sarcoma Thyroid Leukemia Liver Melanoma GU Brain Adenocarcinoma
50 26 3 3 3 2 2 2 1 1 1 1
GU indicates genito-urinary.
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after transfer. In absence of this, the growth of the reconstructed part is dependent on a functional native growth plate.57Y61 The growth areas in the facial skeleton are localized at the level of the maxillary tuberosity (anteroposterior growth), border sutures with the cranium (frontomaxillary, zygomaticomaxillary, zygomaticotemporal, and pterygopalatine) and nasal septum (vertical growth). In the first 7 years of life, expansion of the brain and growth of the eye contribute to the transverse growth of the face. The condyles are the principal determinant of the shape and the direction of the growth of the mandible, they preserve their growth potential up to 20 years of age.62 Additional growth occurs with bone deposition at the posterior aspect of the rami and mandibular body.62 Teeth act as a functional matrix for development of alveolar ridge. The temporalis muscle inf luences the growth of coronoid process and the masseter and medial pterygoid impact ramus growth.63 Growth of the facial skeleton can be adversely affected by procedures involving the facial bones. Although adults with nonsyndromic unrepaired cleft palates exhibit normal facial growth,64,65 up to 25% of patients treated in infancy for cleft palate show evidence of midface retrusion requiring orthognathic surgery.66,67 Maxillary and frontofacial osteotomies in a growing child make secondary corrective procedures very likely68,69; therefore, these are generally deferred until facial growth is completed (17 and 18 years of age for female and male subjects, respectively70). Caterson et al71 reported performing a second Le Fort III procedure in 63% of the syndromic craniosynostosis patients who had undergone early primary subcranial Le Fort III. It should be noted, however, that in the syndromic patients the detrimental consequences of surgery on normal maxillary growth are compounded by a genetically determined lack of midface growth potential. Maxillary growth can be adversely affected as well by separation of the nasal septum and vomer from the maxilla.72,73 Standard mandibular osteotomies have no inf luence on the growth of the mandible.70 However, unimpeded growth of the mandible can accentuate the deformities caused by the arrest of growth after maxillary osteotomies and thus could contribute to the requirement for further secondary procedures.70 Scar tissue formation and vascular compromise seem to be the underlying factors leading to growth retardation of the facial skeleton in nonsyndromic patients.68,74,75
DISCUSSION In the past decade, many milestones have been reached in VCA. The rapidly growing experience in the field proved that the composite tissues can be successfully transplanted under the current immunosuppressive regimens.76 Upper extremity transplantation at different levels of amputation proved to significantly decrease the disability scores, with progressive recovery of the intrinsic muscles in 57% of the patients.77,78 In face transplantation, the restoration of sensation and partial return of motor function has corresponded with significant improvement in the ability to eat, smell, smile, and speak.79,80 An increase in appearance ratings together with decreased anxiety, depression, and chronic pain in these patients has significantly contributed to an improvement in the QoL.81,82 These promising outcomes created the ground for the debate on extending the indications of VCA to pediatric patients, as children display superior nerve recovery due to both central and peripheral factors.83 The distance that axons must travel peripherally is shorter and the nerve regeneration is faster; therefore, muscle reinnervation and sensory recovery of the allograft are expected to occur earlier. In addition, there is greater central plasticity, with better central nervous system adaptation to the new innervation pattern than what occurs in adults.49 Pediatric organ transplantation has traditionally been justified in an attempt to increase survival in patients with end-stage solid organ failure. The benefits of increased survival and improved 448
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physical performance outweigh the risk of complications related to the procedure. Unlike solid organs, pretransplant mortality is not an issue for pediatric recipients of VCA. Therefore, complications related to high cumulative doses of immunosuppression must be considered even more carefully.84 In 2011, tacrolimus represented the main maintenance immunosuppression in pediatric solid organ transplant recipients, associated with mycophenolate mofetil and corticosteroids. The data from the International Registry on Hand and Composite Tissue Transplantation confirm similar regimens used in hand and face transplant recipients.85 Most recipients were healthy young to middle aged adults (19Y52 year-old for hand and 20Y60 year-old for face transplantation). All of the patients experienced episodes of acute rejection. All of the complications related to use of systemic immunosuppression in solid organ transplantation have been witnessed in these patients.85,86 It could be expected that children would experience the same gamut of adverse effects and complications seen in the adult recipients of vascularized composite allografts, rapidly facing an increased risk of infection, renal dysfunction, hypertension, diabetes, malignancies (Table 3),6,85,87 potential growth impairment, and reduced neurocognitive development.28,32 Although pediatric solid organ allograft survival rates have improved over the past years, long-term failure continues to range between 25% and 35%.88 Therefore, with time, an increasing number of patients will require a second transplant. Retransplantation rates for chronic rejection vary between 5% and 25% for all organ types.6 Of all transplant candidates on the waiting list in 2011, 5% to 9% were listed for retransplantation.88 These are sensitized candidates who spend longer times on the waiting lists and are at higher risk for graft loss.89 Although no instances of chronic rejection have been reported in face transplant recipients (longest follow-up being 8 years),85 the first reports on chronic rejection in hand transplantation are now emerging. In the western countries, 5 hands have been amputated (in 4 patients), after chronic rejection. Although a hand transplant recipient could potentially undergo amputation of the transplanted limb, the outcomes after chronic rejection in face transplantation would be potentially even more devastating. In the recent years, there has been an emphasis on minimizing the overall exposure to chronic immunosuppression, to avoid the morbidity associated with these agents. The success of the strategies to induce tolerance has been inconsistent and dependent largely on the type of the organ.38 Schneeberger et al90 recently published the short-term outcomes of a bone marrowYbased protocol to minimize immunosuppression in hand transplantation. All patients experienced 1 to 3 episodes of rejection. Two patients developed evidence of chronic rejection; 1 patient underwent amputation.91 To consider performing VCA in pediatric patients, ideally the growth potential of the allograft should be preserved. On the basis of the results of the review of literature, facial allografts containing a large part of central facial skeleton are at risk for compromised growth because of the osteotomies and resultant scarring involving the principal growth sites of the face. Extremity allografts, on the other hand, would be expected to display normal growth if the epiphyses are preserved and the ischemia time is minimized. However, asymmetric growth in the transplanted extremity compared to the normal extremity, due to the variability in growth rate in different individuals, is also a real possibility. Moreover, it seems that the beneficial effects of younger age on nerve regeneration and recovery of function are present up to the time of adolescence, after which results start to deteriorate.49 To achieve optimal outcomes, both face and hand transplantation procedures should be followed by intensive rehabilitation regimens that might not be fulfilled by pediatric patients and could affect reentry to school. * 2014 Lippincott Williams & Wilkins
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Ultimately, it should be taken into consideration that rejection episodes, hospitalizations, and medication adverse effects all contribute negatively to QoL of the patients3 and the enhancement of the QoL is the main aim of VCA.
CONCLUSIONS On the basis of the accumulated evidence from solid organ transplantation, autologous microsurgical reconstruction, craniofacial procedures, and the growing experience with VCA, it is suggested that it is premature to extend the indications of VCA to pediatric patients. Traditional reconstructive methods should be considered as temporizing or definitive measures in every potential pediatric face transplant candidate (Fig. 1). Considering the high morbidity and mortality related to combined face and double hand or multiple limb transplantation, we caution against performing simultaneous hand and solid organ transplantation. ACKNOWLEDGMENT Informed consent was received for publication of the figures in this article. REFERENCES 1. Kaplan K. Kids to get hand transplants at Boston Children’s Hospital. Los Angeles Times. June 17, 2013. 2. Boston Children’s Hospital. Hand Transplant Program. Available at: http:// articles.latimes.com/2013/jun/17/science/la-sci-sn-hand-transplant-bostonchildrens-20130617. Accessed September 28, 2013. 3. LaRosa C, Baluarte HJ, Meyers KE. Outcomes in pediatric solid-organ transplantation. Pediatr Transplant. 2011;15:128Y141. 4. Silverstein DM, Mitchell M, LeBlanc P, et al. Assessment of risk factors for cardiovascular disease in pediatric renal transplant patients. Pediatr Transplant. 2007;11:721Y729. 5. Sharif A, Baboolal K. Metabolic syndrome and solid-organ transplantation. Am J Transplant. 2010;10:12Y17. 6. Kelly DA. Current issues in pediatric transplantation. Pediatr Transplant. 2006;10:712Y720. 7. Schonder KS, Mazariegos GV, Weber RJ. Adverse effects of immunosuppression in pediatric solid organ transplantation. Paediatr Drugs. 2010; 12:35Y49. 8. Sorof JM, Sullivan EK, Tejani A, et al. Antihypertensive medication and renal allograft failure: a North American Pediatric Renal Transplant Cooperative Study report. J Am Soc Nephrol. 1999;10:1324Y1330. 9. Siirtola A, Antikainen M, Ala-Houhala M, et al. Serum lipids in children 3 to 5 years after kidney, liver, and heart transplantation. Transpl Int. 2004;17:109Y119. 10. Cosio FG, Pesavento TE, Osei K, et al. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int. 2001;59:732Y737. 11. Campbell KM, Yazigi N, Ryckman FC, et al. High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation. J Pediatr. 2006;148:475Y480. 12. Bartosh SM, Alonso EM, Whitington PF. Renal outcomes in pediatric liver transplantation. Clin Transplant. 1997;11:354Y360. 13. Kim S, Webster AC, Craig JC. Current trends in immunosuppression following organ transplantation in children. Curr Opin Organ Transplant, 2013. 14. Roche SL, Kaufmann J, Dipchand AI, et al. Hypertension after pediatric heart transplantation is primarily associated with immunosuppressive regimen. J Heart Lung Transplant. 2008;27:501Y507. 15. Bloom RD, Reese PP. Chronic kidney disease after nonrenal solid-organ transplantation. J Am Soc Nephrol. 2007;18:3031Y3041. 16. Robinson PD, Shroff RC, Spencer H. Renal complications following lung and heart-lung transplantation. Pediatr Nephrol. 2013;28:375Y386. 17. Fryer JP, Benedetti E, Gillingham K, et al. Steroid-related complications in pediatric kidney transplant recipients in the cyclosporine era. Transplant Proc. 1994;26:91Y92. 18. Fonseca-Aten M, Michaels MG. Infections in pediatric solid organ transplant recipients. Semin Pediatr Surg. 2006;15:153Y161.
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19. Dharnidharka VR, Stablein DM, Harmon WE. Post-transplant infections now exceed acute rejection as cause for hospitalization: a report of the NAPRTCS. Am J Transplant. 2004;4:384Y389. 20. Rubin RH. Cytomegalovirus in solid organ transplantation. Transpl Infect Dis. 2001;3(suppl 2):1Y5. 21. Cockfield SM. Identifying the patient at risk for post-transplant lymphoproliferative disorder. Transpl Infect Dis. 2001;3:70Y78. 22. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998;338:1741Y1751. 23. Paramesh A, Cannon R, Buell JF. Malignancies in pediatric solid organ transplant recipients: epidemiology, risk factors, and prophylactic approaches. Curr Opin Organ Transplant. 2010;15:621Y627. 24. Penn I. De novo malignances in pediatric organ transplant recipients. Pediatr Transplant. 1998;2:56Y63. 25. Buell JF, Gross TG, Thomas MJ, et al. Malignancy in pediatric transplant recipients. Semin Pediatr Surg. 2006;15:179Y187. 26. Kirk AD, Cherikh WS, Ring M, et al. Dissociation of depletional induction and posttransplant lymphoproliferative disease in kidney recipients treated with alemtuzumab. Am J Transplant. 2007;7:2619Y2625. 27. Coutinho HM, Groothoff JW, Offringa M, et al. De novo malignancy after paediatric renal replacement therapy. Arch Dis Child. 2001;85:478Y483. 28. Vasudevan A, Phadke K. Growth in pediatric renal transplant recipients. Transplant Proc. 2007;39:753Y755. 29. Helenius I, Jalanko H, Remes V, et al. Scoliosis after solid organ transplantation in children and adolescents. Am J Transplant. 2006;6:324Y330. 30. Helenius I, Remes V, Salminen S, et al. Incidence and predictors of fractures in children after solid organ transplantation: a 5-year prospective, populationbased study. J Bone Miner Res. 2006;21:380Y387. 31. Alonso EM, Sorensen LG. Cognitive development following pediatric solid organ transplantation. Curr Opin Organ Transplant. 2009;14:522Y525. 32. Krull K, Fuchs C, Yurk H, et al. Neurocognitive outcome in pediatric liver transplant recipients. Pediatr Transplant. 2003;7:111Y118. 33. Berney-Martinet S, Key F, Bell L, et al. Psychological profile of adolescents with a kidney transplant. Pediatr Transplant. 2009;13:701Y710. 34. Hsu DT. Biological and psychological differences in the child and adolescent transplant recipient. Pediatr Transplant. 2005;9:416Y421. 35. Sudan DL, Shaw BW Jr, Langnas AN. Causes of late mortality in pediatric liver transplant recipients. Ann Surg. 1998;227:289Y295. 36. Anthony SJ, Pollock Barziv S, Ng VL. Quality of life after pediatric solid organ transplantation. Pediatr Clin North Am. 2010;57:559Y574, table of contents. 37. Zamora I. Advances in kidney transplantation in children. An Esp Pediatr. 1997;Spec No 1:25Y26. 38. Seyfert-Margolis V, Feng S. Tolerance: is it achievable in pediatric solid organ transplantation?Pediatr Clin North Am. 2010;57:523Y538, table of contents. 39. Mazariegos GV, Sindhi R, Thomson AW, et al. Clinical tolerance following liver transplantation: long term results and future prospects. Transpl Immunol. 2007;17:114Y119. 40. Koshiba T, Li Y, Takemura M, et al. Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol. 2007;17:94Y97. 41. Yoshitomi M, Koshiba T, Haga H, et al. Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation. Transplantation. 2009;87:606Y614. 42. Van Beek AL, Wavak PW, Zook EG. Microvascular surgery in young children. Plast Reconstr Surg. 1979;63:457Y462. 43. McC O’Brien B, Franklin JD, Morrison WA, et al. Replantation and revascularisation surgery in children. Hand. 1980;12:12Y24. 44. Sekiguchi J, Ohmori K. Youngest replantation with microsurgical anastomoses. Hand. 1979;11:64Y68. 45. Demiri E, Bakhach J, Tsakoniatis N, et al. Bone growth after replantation in children. J Reconstr Microsurg. 1995;11:113Y122; discussion 122-3. 46. Chang J, Jones NF. Radiographic analysis of growth in pediatric microsurgical toe-to-hand transfers. Plast Reconstr Surg. 2002;109:576Y582. 47. Ikeda K, Yamauchi S, Hashimoto F, et al. Digital replantation in children: a long-term follow-up study. Microsurgery. 1990;11:261Y264. 48. Upton J, Guo L, Labow BI. Pediatric free-tissue transfer. Plast Reconstr Surg. 2009;124:e313Ye326.
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49. Chemnitz A, Bjo¨rkman A, Dahlin LB, et al. Functional outcome thirty years after median and ulnar nerve repair in childhood and adolescence. J Bone Joint Surg Am. 2013;95:329Y337. 50. Duteille F, Petry D, Dautel G, et al. A comparison between clinical results and electromyographic analysis after median or ulnar nerve injuries in children’s wrists. Ann Plast Surg. 2001;46:382Y386. 51. Upton J, Guo L. Pediatric free tissue transfer: a 29-year experience with 433 transfers. Plast Reconstr Surg. 2008;121:1725Y1737. 52. Chiang YC, Jeng SF, Yeh MC, et al. Free tissue transfer for leg reconstruction in children. Br J Plast Surg. 1997;50:335Y342. 53. Gharb BB, Salgado CJ, Moran SL, et al. Free anterolateral thigh flap in pediatric patients. Ann Plast Surg. 2011;66:143Y147. 54. Mast BA, Newton ED. Aggressive use of free flaps in children for burn scar contractures and other soft-tissue deficits. Ann Plast Surg. 1996;36:569Y575. 55. Lin CH, Mardini S, Wei FC, et al. Free flap reconstruction of foot and ankle defects in pediatric patients: long-term outcome in 91 cases. Plast Reconstr Surg. 2006;117:2478Y2487. 56. Song JW, Ben-Nakhi M, Hong JP. Reconstruction of lower extremity with perforator free flaps by free style approach in pediatric patients. J Reconstr Microsurg. 2012;28:589Y594. 57. Crosby MA, Martin JW, Robb GL, et al. Pediatric mandibular reconstruction using a vascularized fibula flap. Head Neck. 2008;30:311Y319. 58. Innocenti M, Delcroix L, Manfrini M, et al. Vascularized proximal fibular epiphyseal transfer for distal radial reconstruction. J Bone Joint Surg Am. 2005;87(suppl 1):237Y246. 59. Innocenti M, Delcroix L, Romano GF, et al. Vascularized epiphyseal transplant. Orthop Clin North Am. 2007;38:95Y101vii. 60. Bianchi B, Ferri A, Ferrari S, et al. Microvascular reconstruction of mandibular defects in paediatric patients. J Craniomaxillofac Surg. 2011;39:289Y295. 61. Schwarz GS, Disa JJ, Mehrara BJ, et al. Reconstruction of oncologic tibial defects in children using vascularized fibula flaps. Plast Reconstr Surg. 2012;129:195Y206. 62. Ranly DM. Craniofacial growth. Dent Clin North Am. 2000;44:457Y470v. 63. Galella S, Chow D, Jones E, et al. Guiding atypical facial growth back to normal. Part 1: Understanding facial growth. Int J Orthod Milwaukee. 2011;22:47Y54. 64. Ortiz-Monasterio F, Serrano A, Barrera G, et al. A study of untreated adult cleft palate patients. Plast Reconstr Surg. 1966;38:36Y41. 65. Shetye PR. Facial growth of adults with unoperated clefts. Clin Plast Surg. 2004;31:361Y371. 66. Cohen SR, Corrigan M, Wilmot J, et al. Cumulative operative procedures in patients aged 14 years and older with unilateral or bilateral cleft lip and palate. Plast Reconstr Surg. 1995;96:267Y271. 67. Rosenstein S, Kernahan D, Dado D, et al. Orthognathic surgery in cleft patients treated by early bone grafting. Plast Reconstr Surg. 1991;87:835Y892; discussion 840-2. 68. Warren SM, Shetye PR, Obaid SI, et al. Long-term evaluation of midface position after Le Fort III advancement: a 20-plus-year follow-up. Plast Reconstr Surg. 2012;129:234Y242. 69. Ko EW, Chen PK, Tai IC, et al. Fronto-facial monobloc distraction in syndromic craniosynostosis. Three-dimensional evaluation of treatment outcome and facial growth. Int J Oral Maxillofac Surg. 2012;41:20Y27.
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70. Freihofer HP Jr. Results of osteotomies of the facial skeleton in adolescence. J Maxillofac Surg. 1977;5:267Y297. 71. Caterson EJ, Shetye PR, Grayson BH, et al. Surgical management of patients with a history of early Le Fort III advancement after they have attained skeletal maturity. Plast Reconstr Surg. 2013;132:592eY601e. 72. Grymer LF, Bosch C. The nasal septum and the development of the midface. A longitudinal study of a pair of monozygotic twins. Rhinology. 1997;35:6Y10. 73. Ousterhout DK, Vargervik K. Maxillary hypoplasia secondary to midfacial trauma in childhood. Plast Reconstr Surg. 1987;80:491Y499. 74. Wolford LM, Cassano DS, Cottrell DA, et al. Orthognathic surgery in the young cleft patient: preliminary study on subsequent facial growth. J Oral Maxillofac Surg. 2008;66:2524Y2536. 75. Precious DS, Delaire J, Hoffman CD. The effects of nasomaxillary injury on future facial growth. Oral Surg Oral Med Oral Pathol. 1988;66:525Y530. 76. Siemionow MZ, Gharb BB, Rampazzo A. Successes and lessons learned after more than a decade of upper extremity and face transplantation. Curr Opin Organ Transplant. 2013;18:633Y639. 77. Jablecki J, Kaczmarzyk L, Domanasiewicz A, et al. Result of arm-level upperlimb transplantation in two recipients at 19- and 30-month follow-up. Ann Transplant. 2012;17:126Y132. 78. Landin L, Bonastre J, Casado-Sanchez C, et al. Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review. Transpl Int. 2012;25:424Y432. 79. Shanmugarajah K, Hettiaratchy S, Butler PE. Facial transplantation. Curr Opin Otolaryngol Head Neck Surg. 2012;20:291Y297. 80. Siemionow M, Gharb BB, Rampazzo A. Pathways of sensory recovery after face transplantation. Plast Reconstr Surg. 2011;127:1875Y1889. 81. Coffman KL, Siemionow MZ. Face transplantation: psychological outcomes at three-year follow-up. Psychosomatics. 2013;54:372Y378. 82. Chang G, Pomahac B. Psychosocial changes 6 months after face transplantation. Psychosomatics. 2013;54:367Y371. 83. Bolitho DG, Boustred M, Hudson DA, et al. Primary epineural repair of the ulnar nerve in children. J Hand Surg Am. 1999;24:16Y20. 84. Campbell KM, Bucuvalas JC. Renal function in the long term after pediatric liver transplantation: is there a need for protocol kidney biopsies? Curr Opin Organ Transplant. 2010;15:608Y613. 85. Petruzzo P, Dubernard JM, Lanzetta M. International Registry on Hand and Composite Tissue Transplantation. Available at: https://www.handregistry.com. 2013. 86. Khalifian S, Brazio PS, Mohan R, et al. Facial transplantation: the first 9 years. Lancet. 2014. 87. Petruzzo P, Dubernard JM. The International Registry on Hand and Composite Tissue allotransplantation. Clin Transpl. 2011: 247Y253. 88. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients. OPTN/SRTR 2011 Annual Report. OPTN/ SRTR 2011 Annual Data Report 2012:1Y234. 89. Girnita AL, Webber SA, Zeevi A. Anti-HLA alloantibodies in pediatric solid organ transplantation. Pediatr Transplant. 2006;10:146Y153. 90. Schneeberger S, Gorantla VS, Brandacher G, et al. Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression. Ann Surg. 2013;257:345Y351. 91. Lee AW. Composite Tissue Transfer in 2013: An Update. 2013; ASSH Instructional Courses.
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Pediatric Vascularized Composite Allotransplantation Gaby Doumit, MD, MSc, Bahar Bassiri Gharb, MD, PhD, Antonio Rampazzo, MD, PhD, Francis Papay, MD, Maria Z. Siemionow, MD, PhD, DSc, and James E. Zins, MD Background: Vascularized composite allotransplantation (VCA) has experienced a growing acceptance, which has led to a debate centered on extending the indications of the procedure to include pediatric patients. The aim of this article was to discuss such indications based on the evidence in pediatric solid organ transplantation, reconstructive surgery in children, and VCA in adult patients. Methods: Papers published on the outcomes of pediatric solid organ transplantation, growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, facial fractures, and outcomes after repair of peripheral nerves in children were reviewed. Results: Although the outcomes of solid organ transplantation in children have improved, the transplanted organs continue to have a limited lifespan. Long-term immunosuppressive therapy exposes the patients to an increased lifetime risk of infections, diabetes, hypertension, dyslipidemia, cardiovascular disease, and malignancy. Growth impairment and learning disabilities are other relevant drawbacks, which affect the pediatric recipients. Nonadherence to medication is a common cause of graft dysfunction and loss among the adolescent transplant recipients. Rejection episodes, hospitalizations, and medication adverse effects contribute negatively to the quality of life of the patients. Although normal growth after limb transplantation could be expected, pediatric facial transplant recipients may present with arrest of growth of transplanted midfacial skeleton. Conclusions: Considering the nonYlife-threatening nature of the conditions that lead to eligibility for VCA, it is suggested that it is premature to extend the indications of VCA to include pediatric patients under the currently available immunosuppressive protocols. Key Words: pediatric vascularized composite allotransplantation, vascularized composite allotransplantation, VCA, face transplantation, hand transplantation, microsurgery, reconstructive surgery, children (Ann Plast Surg 2014;73: 445Y450)
W
ith more than 150 vascularized composite allotransplants performed worldwide, many of the technical, logistic, and ethical aspects of the procedure have been addressed. Acceptable graft survival and functional outcomes have been achieved under the current immunosuppressive regimens, creating the ground for a gradual extension of the indications for vascularized composite allotransplantation (VCA). Although allotransplantation of nonvital organs is a controversial issue, pediatric VCA is an even greater subject of debate. Boston Children’s Hospital recently announced the establishment of the first pediatric hand transplantation program in the world.1 Patients between 10 and 25 years of age who had lost both hands, or who missed only 1 hand but either were already on immunosuppressive medication for a solid organ transplant or had a poorly
Received February 9, 2014, and accepted for publication, after revision, June 5, 2014. From the Dermatology and Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH. Conflicts of interest and sources of funding: The authors have no conflict of interests to disclose. This project was supported by institutional funds. Reprints: Gaby Doumit, MD, MSc, Dermatology and Plastic Surgery Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195. E-mail: [email protected]. Copyright * 2014 by Lippincott Williams & Wilkins ISSN: 0148-7043/14/7304-0445 DOI: 10.1097/SAP.0000000000000300
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functioning contralateral hand were being considered eligible for hand transplantation.2 Of note, as one of the institutions with institutional review board approval for face transplantation, our center has also been receiving referrals for pediatric face transplantation (Fig. 1). The evidence derived from pediatric solid organ transplantation proves that children pose unique challenges, which transcend the technical and immunological feasibility issues. Ideally, in the event of transplantation, the composite allograft should preserve the potential to grow with the recipient to achieve optimal restoration of function and form and to avoid multiple secondary procedures. In the present study, the current evidence on the outcomes of solid organ transplantation in children is summarized and the possible deleterious effects of the allotransplantation in pediatric recipients are elucidated. The potential for growth of the composite allografts after transfer is examined and the lessons learned from the global experience with VCA in adults are discussed with special regard to aspects relevant to pediatric patients.
MATERIALS AND METHODS Search Strategy and Selection Criteria Comprehensive MEDLINE search was performed in the English literature for peer-reviewed articles, published between 2005 and 2013, on the state of art of solid organ transplantation in pediatric patients. A second MEDLINE search was performed to retrieve papers on the growth after replantation of extremities, vascularized autologous tissue transfer, craniofacial surgery, orthognathic procedures, and facial fractures in pediatric patients. Finally, we searched for papers detailing the outcomes after repair of peripheral nerves in children. The keywords used in the search are summarized in Table 1.
RESULTS Pediatric Organ Transplantation General Outcomes Five- and 10-year allograft survival rates have dramatically improved during the last several years3 (Table 2). With both longer allograft and patient survival, adverse outcomes have been increasingly witnessed (Table 3). Among pediatric recipients of solid organ transplants, the cardiovascular disease risk factors are exponentially increased with the ensuing cardiovascular morbidities threatening both graft and patient survival4,5 (Table 3).6 Hypertension usually occurs within the first year after transplantation and persists into adulthood.7 Older than 12 years at the time of transplantation, presence of intact native kidneys, at least 1 episode of acute rejection, and cadaveric allograft all correlate with an increased risk of developing hypertension after transplantation.8 Dyslipidemia is another significant contributor to cardiovascular disease in children. The prevalence is increased in the first year affecting between 26% and 56% of pediatric solid organ recipients.9 Posttransplantation diabetes affects between 2.6% and 17% of pediatric transplant patients7 and the incidence increases with time after transplantation.10 The incidence of renal dysfunction in nonrenal transplants has been reported between 24% and 70%.11,12 www.annalsplasticsurgery.com
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Steroids are associated with significant dose-dependent and cumulative toxicity.17 In particular, children who receive chronic steroids are more prone to growth retardation despite minimizing cumulative dosing.
Infectious Disease Age is an important determinant of susceptibility to infection and disease severity.18 Infections are the most common cause of death (28.6%) and hospitalization19 among pediatric renal transplant recipients.3 Often young children lack immunity to many pathogens before transplantation and are at higher risk of acquiring primary infection with many organisms after they are immunosuppressed, leading to increased morbidity.20,21 Both Epstein-Barr virus (EBV) and cytomegalovirus have been associated with indirect immunomodulatory effects leading to an enhanced susceptibility to other opportunistic infections, PTLD, as well as an increased risk of graft rejection.22 Primary EBV infection is the most clearly defined risk factor for the development of early PTLD, and children are at considerably higher risk of developing PTLD than adults as they are often EBV naive at the time of transplantation.21
Malignancy
FIGURE 1. A 15-year-old adolescent girl was referred to our department for an opinion regarding face transplantation. In 2008, she was diagnosed with fibrous dysplasia and had undergone 9 debulking procedures in other major academic centers during the past 4 years. The mass obliterated the nose and extended 9 cm anterior to the facial plane. Her nostril opening measured 4 5 cm bilaterally. Her bilateral orbits were displaced laterally and superiorly resulting in hypertelorism, dystopia, and proptosis. Her maxilla, zygoma, and maxillary alveolus were also severely deformed. Her vision and facial nerve function were intact. As the institutional review board protocol for face transplant at our institution is presently not approved for patients younger than 18 years, a decision was made for surgical resection of the tumor and temporary reconstruction with titanium mesh plates given the aggressive nature of the disease. At 1-year follow-up, there was no evidence of recurrence. The patient was quite satisfied with her appearance. Intranasal examination demonstrated mucosalization of the titanium mesh.
Immunosuppressive Treatment Current immunosuppression protocols typically involve 4 agents, namely, an induction agent, corticosteroids, an antimetabolite (mycophenolate mofetil) and a calcineurin inhibitor (cyclosporine, tacrolimus).13 The efficacy of these regimens is demonstrated by the low retransplantation rates for chronic rejection, which vary between 5% and 25% for all organ types.6 Interleukine-2 antagonists (basiliximab and daclizumab) remain the preferred induction agents in children given the higher risk of posttransplant lymphoproliferative disease (PTLD) and cytomegalovirus disease seen with T-cellYdepleting agents (antithymoglobulin and OK3). Calcineurin inhibitors are the main risk factors for posttransplant hypertension, with an increased risk when steroids are coadministered.14 Cyclosporine and tacrolimus can lead both to acute and chronic nephrotoxicity.15,16 446
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Children remain one of the most vulnerable populations for developing cancer posttransplantation, especially because of immune naivety and longer exposure to immunosuppression.23 The incidence of cancer among pediatric transplant recipients is as high as 10 times the incidence for the nontransplanted same age group.24 The incidence of nonskin malignancy after 10 years of chronic immunosuppression in all solid organ recipients has been estimated at 20%, with a greater than 40% incidence after 20 years.25 Currently, malignancies are the second most common cause of transplant recipients’ mortality.23 Among pediatric solid organ transplant recipients, PTLD remains the most common neoplasm (50%).23,25 The risk of PTLD is 3.7-fold higher in the pediatric transplant population with an incidence of 2.2% compared to 0.4% in adults.26 Skin cancers, especially squamous and basal cell carcinomas are the second most common malignancies (26%) in the pediatric population (Table 4).25,27
Growth and Orthopedic Complications Normal development can be delayed in pediatric recipients of solid organs, with deficiencies encountered both in physical stature as well as cognitive and psychosocial functions. Younger age at the time of transplantation, graft dysfunction, acute rejection, and use of corticosteroids are some of the risk factors for growth impairment.28 Transplantation and immunosuppressive medications increase the risk of fractures and avascular necrosis, delay the growth and cause TABLE 1. Keywords Used for Literature Search Solid organ transplantation in children Pediatric solid organ transplantation Free flaps in children Free tissue transfer in children Free fibula in children Toe to hand transfer Replantation in children Growth after orthognathic surgery Growth after facial fractures Growth after Le Fort Outcomes nerve repair in children
and Outcomes and Outcomes or Pediatric or Pediatric or Pediatric and Growth and Growth
or Pediatric
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TABLE 2. Long-term Adverse Outcomes in Pediatric Solid Organ Allotransplantation Organ
5-y Survival, %
10-y Survival, %
Liver Kidney Heart
68Y75 68Y84 68Y75
80Y85 80 60Y80
In kidney transplant recipients, it is not possible to differentiate long-term nephrotoxicity from chronic rejection.
pathologic development of the spine.29 Compared with age-matched controls, the incidence of fractures in allograft recipients is 6-fold higher.30
Cognitive Development and Psychiatric Issues Current studies support that neurocognitive delay is an important problem in children receiving organ transplants; however, this could be related to the severity of chronic organ failure pretransplantation.31 Both liver and kidney transplant survivors are in the low interquartile range compared to their peers and complain of memory lapses and poor concentration.32 Various psychological outcomes such as depression, anxiety, and even frank psychiatric disorders have been reported to occur frequently among pediatric transplant recipients.33 The need for independence, typical of the adolescence, coupled with a notion of invulnerability often leads to nonadherence34 to medications. This has been reported ranging between 15% and 22%34 and is the major cause of graft loss or rejection in adolescent transplant recipients.35
Quality of Life Solid organ transplant recipients usually have improved quality of life (QoL) compared to pretransplant period and lower QoL compared to healthy peers.36 Prevailing concerns affecting QoL after transplantation are physical symptoms, body image, school disruption, and strained family/peer relationships. Rejection episodes, hospitalizations, and medication adverse effects all contribute negatively to QoL.3 Zamora37 reported that the majority of young adults with childhood renal transplants lived with their parents, had no type of sexual relationship, and perceived their future as limited and remained anxious about possible organ rejection, despite being in good health.
University of Pittsburgh reported that operational tolerance after pediatric liver transplantation was achieved in nearly 20% of selected patient populations. Despite 29% of the patients developing proven rejection, none of the patients lost the allograft.39 University of Kyoto40 achieved a 15% complete withdrawal of immunosuppression in their cohort of 581 pediatric liver transplant recipients. Noteworthy, tolerant patients, despite normal liver function, exhibited a decrease in size and an increase in number of bile ducts, as well as a higher degree of fibrosis. These findings reveal that the risk of chronic rejection could be significantly higher in these patients in the long run.41
Growth Potential After Reconstructive Procedures in Children Continued skeletal growth is usually observed in the amputated parts after replantation if the growth plates are not injured.42Y45 Growth rates in digital replantation have been reported being more favorable than those in major limb replantation: 88% to 100% and 75% to 96% of the noninjured side, respectively.45 Chang and Jones46 showed preserved growth potential in pediatric toe to hand transfer with equal length of the transferred and contralateral toe. The duration of ischemia has been shown to affect adversely the growth after replantation, with normal bone growth attained when ischemia time did not exceed 3 hours.45 Recovery of sensation has been reported to occur faster than in adults, with near normal 2-point discrimination and light touch in pediatric digital replantation and vascularized toe to hand transfer.47,48 Chemnitz et al49 compared the functional outcome after complete injuries to median and ulnar nerves in childhood (G12 years) and adolescence (12Y20 years), showing superior sensory and motor recovery in childhood injuries. Similar results were reported by Duteille et al,50 who studied 38 median and ulnar nerve injuries at wrist level, confirming a markedly superior sensory recovery in children. Fasciocutaneous free f laps retain the growth characteristics of the donor site, including hair and bulk.51 No obvious difference in the growth rate between fasciocutaneous f laps, muscle f laps with split-thickness skin graft, and myocutaneous flaps has been demonstrated.52 The children display an increased tendency toward hypertrophic scarring53 and a high rate of secondary procedures are necessary to correct the scar contracture developing along the margins of the f lap (16%Y39%).54Y56 Vascularized bone transfer, for reconstruction of mandibular or extremity defects, has shown that the preservation of the epiphyseal growth plate is necessary to allow continued growth TABLE 4. Malignancies in Pediatric Organ Transplant Recipients
Tolerance Many of the protocols to induce tolerance have not included pediatric transplant candidates.38 In one of the few pediatric trials, the TABLE 3. Long-term Allograft Survival in Pediatric Solid Organ Transplantation Hypertension Dyslipidemia Diabetes Nephrotoxicity PTLD Malignancy Retransplantation rate
Pediatric VCA
Liver, %
Kidney, %
Heart, %
28 26 5 5 5Y7 12 5Y10
70 56 2.6 NA 7 17 25
35 40 17 4 17 1Y4 5
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Type of Tumor
Percent of Total Tumors Reported
PTLD Nonmelanoma skin cancer Gynecologic Kaposi sarcoma Sarcoma Thyroid Leukemia Liver Melanoma GU Brain Adenocarcinoma
50 26 3 3 3 2 2 2 1 1 1 1
GU indicates genito-urinary.
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after transfer. In absence of this, the growth of the reconstructed part is dependent on a functional native growth plate.57Y61 The growth areas in the facial skeleton are localized at the level of the maxillary tuberosity (anteroposterior growth), border sutures with the cranium (frontomaxillary, zygomaticomaxillary, zygomaticotemporal, and pterygopalatine) and nasal septum (vertical growth). In the first 7 years of life, expansion of the brain and growth of the eye contribute to the transverse growth of the face. The condyles are the principal determinant of the shape and the direction of the growth of the mandible, they preserve their growth potential up to 20 years of age.62 Additional growth occurs with bone deposition at the posterior aspect of the rami and mandibular body.62 Teeth act as a functional matrix for development of alveolar ridge. The temporalis muscle inf luences the growth of coronoid process and the masseter and medial pterygoid impact ramus growth.63 Growth of the facial skeleton can be adversely affected by procedures involving the facial bones. Although adults with nonsyndromic unrepaired cleft palates exhibit normal facial growth,64,65 up to 25% of patients treated in infancy for cleft palate show evidence of midface retrusion requiring orthognathic surgery.66,67 Maxillary and frontofacial osteotomies in a growing child make secondary corrective procedures very likely68,69; therefore, these are generally deferred until facial growth is completed (17 and 18 years of age for female and male subjects, respectively70). Caterson et al71 reported performing a second Le Fort III procedure in 63% of the syndromic craniosynostosis patients who had undergone early primary subcranial Le Fort III. It should be noted, however, that in the syndromic patients the detrimental consequences of surgery on normal maxillary growth are compounded by a genetically determined lack of midface growth potential. Maxillary growth can be adversely affected as well by separation of the nasal septum and vomer from the maxilla.72,73 Standard mandibular osteotomies have no inf luence on the growth of the mandible.70 However, unimpeded growth of the mandible can accentuate the deformities caused by the arrest of growth after maxillary osteotomies and thus could contribute to the requirement for further secondary procedures.70 Scar tissue formation and vascular compromise seem to be the underlying factors leading to growth retardation of the facial skeleton in nonsyndromic patients.68,74,75
DISCUSSION In the past decade, many milestones have been reached in VCA. The rapidly growing experience in the field proved that the composite tissues can be successfully transplanted under the current immunosuppressive regimens.76 Upper extremity transplantation at different levels of amputation proved to significantly decrease the disability scores, with progressive recovery of the intrinsic muscles in 57% of the patients.77,78 In face transplantation, the restoration of sensation and partial return of motor function has corresponded with significant improvement in the ability to eat, smell, smile, and speak.79,80 An increase in appearance ratings together with decreased anxiety, depression, and chronic pain in these patients has significantly contributed to an improvement in the QoL.81,82 These promising outcomes created the ground for the debate on extending the indications of VCA to pediatric patients, as children display superior nerve recovery due to both central and peripheral factors.83 The distance that axons must travel peripherally is shorter and the nerve regeneration is faster; therefore, muscle reinnervation and sensory recovery of the allograft are expected to occur earlier. In addition, there is greater central plasticity, with better central nervous system adaptation to the new innervation pattern than what occurs in adults.49 Pediatric organ transplantation has traditionally been justified in an attempt to increase survival in patients with end-stage solid organ failure. The benefits of increased survival and improved 448
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physical performance outweigh the risk of complications related to the procedure. Unlike solid organs, pretransplant mortality is not an issue for pediatric recipients of VCA. Therefore, complications related to high cumulative doses of immunosuppression must be considered even more carefully.84 In 2011, tacrolimus represented the main maintenance immunosuppression in pediatric solid organ transplant recipients, associated with mycophenolate mofetil and corticosteroids. The data from the International Registry on Hand and Composite Tissue Transplantation confirm similar regimens used in hand and face transplant recipients.85 Most recipients were healthy young to middle aged adults (19Y52 year-old for hand and 20Y60 year-old for face transplantation). All of the patients experienced episodes of acute rejection. All of the complications related to use of systemic immunosuppression in solid organ transplantation have been witnessed in these patients.85,86 It could be expected that children would experience the same gamut of adverse effects and complications seen in the adult recipients of vascularized composite allografts, rapidly facing an increased risk of infection, renal dysfunction, hypertension, diabetes, malignancies (Table 3),6,85,87 potential growth impairment, and reduced neurocognitive development.28,32 Although pediatric solid organ allograft survival rates have improved over the past years, long-term failure continues to range between 25% and 35%.88 Therefore, with time, an increasing number of patients will require a second transplant. Retransplantation rates for chronic rejection vary between 5% and 25% for all organ types.6 Of all transplant candidates on the waiting list in 2011, 5% to 9% were listed for retransplantation.88 These are sensitized candidates who spend longer times on the waiting lists and are at higher risk for graft loss.89 Although no instances of chronic rejection have been reported in face transplant recipients (longest follow-up being 8 years),85 the first reports on chronic rejection in hand transplantation are now emerging. In the western countries, 5 hands have been amputated (in 4 patients), after chronic rejection. Although a hand transplant recipient could potentially undergo amputation of the transplanted limb, the outcomes after chronic rejection in face transplantation would be potentially even more devastating. In the recent years, there has been an emphasis on minimizing the overall exposure to chronic immunosuppression, to avoid the morbidity associated with these agents. The success of the strategies to induce tolerance has been inconsistent and dependent largely on the type of the organ.38 Schneeberger et al90 recently published the short-term outcomes of a bone marrowYbased protocol to minimize immunosuppression in hand transplantation. All patients experienced 1 to 3 episodes of rejection. Two patients developed evidence of chronic rejection; 1 patient underwent amputation.91 To consider performing VCA in pediatric patients, ideally the growth potential of the allograft should be preserved. On the basis of the results of the review of literature, facial allografts containing a large part of central facial skeleton are at risk for compromised growth because of the osteotomies and resultant scarring involving the principal growth sites of the face. Extremity allografts, on the other hand, would be expected to display normal growth if the epiphyses are preserved and the ischemia time is minimized. However, asymmetric growth in the transplanted extremity compared to the normal extremity, due to the variability in growth rate in different individuals, is also a real possibility. Moreover, it seems that the beneficial effects of younger age on nerve regeneration and recovery of function are present up to the time of adolescence, after which results start to deteriorate.49 To achieve optimal outcomes, both face and hand transplantation procedures should be followed by intensive rehabilitation regimens that might not be fulfilled by pediatric patients and could affect reentry to school. * 2014 Lippincott Williams & Wilkins
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Ultimately, it should be taken into consideration that rejection episodes, hospitalizations, and medication adverse effects all contribute negatively to QoL of the patients3 and the enhancement of the QoL is the main aim of VCA.
CONCLUSIONS On the basis of the accumulated evidence from solid organ transplantation, autologous microsurgical reconstruction, craniofacial procedures, and the growing experience with VCA, it is suggested that it is premature to extend the indications of VCA to pediatric patients. Traditional reconstructive methods should be considered as temporizing or definitive measures in every potential pediatric face transplant candidate (Fig. 1). Considering the high morbidity and mortality related to combined face and double hand or multiple limb transplantation, we caution against performing simultaneous hand and solid organ transplantation. ACKNOWLEDGMENT Informed consent was received for publication of the figures in this article. REFERENCES 1. Kaplan K. Kids to get hand transplants at Boston Children’s Hospital. Los Angeles Times. June 17, 2013. 2. Boston Children’s Hospital. Hand Transplant Program. Available at: http:// articles.latimes.com/2013/jun/17/science/la-sci-sn-hand-transplant-bostonchildrens-20130617. Accessed September 28, 2013. 3. LaRosa C, Baluarte HJ, Meyers KE. Outcomes in pediatric solid-organ transplantation. Pediatr Transplant. 2011;15:128Y141. 4. Silverstein DM, Mitchell M, LeBlanc P, et al. Assessment of risk factors for cardiovascular disease in pediatric renal transplant patients. Pediatr Transplant. 2007;11:721Y729. 5. Sharif A, Baboolal K. Metabolic syndrome and solid-organ transplantation. Am J Transplant. 2010;10:12Y17. 6. Kelly DA. Current issues in pediatric transplantation. Pediatr Transplant. 2006;10:712Y720. 7. Schonder KS, Mazariegos GV, Weber RJ. Adverse effects of immunosuppression in pediatric solid organ transplantation. Paediatr Drugs. 2010; 12:35Y49. 8. Sorof JM, Sullivan EK, Tejani A, et al. Antihypertensive medication and renal allograft failure: a North American Pediatric Renal Transplant Cooperative Study report. J Am Soc Nephrol. 1999;10:1324Y1330. 9. Siirtola A, Antikainen M, Ala-Houhala M, et al. Serum lipids in children 3 to 5 years after kidney, liver, and heart transplantation. Transpl Int. 2004;17:109Y119. 10. Cosio FG, Pesavento TE, Osei K, et al. Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years. Kidney Int. 2001;59:732Y737. 11. Campbell KM, Yazigi N, Ryckman FC, et al. High prevalence of renal dysfunction in long-term survivors after pediatric liver transplantation. J Pediatr. 2006;148:475Y480. 12. Bartosh SM, Alonso EM, Whitington PF. Renal outcomes in pediatric liver transplantation. Clin Transplant. 1997;11:354Y360. 13. Kim S, Webster AC, Craig JC. Current trends in immunosuppression following organ transplantation in children. Curr Opin Organ Transplant, 2013. 14. Roche SL, Kaufmann J, Dipchand AI, et al. Hypertension after pediatric heart transplantation is primarily associated with immunosuppressive regimen. J Heart Lung Transplant. 2008;27:501Y507. 15. Bloom RD, Reese PP. Chronic kidney disease after nonrenal solid-organ transplantation. J Am Soc Nephrol. 2007;18:3031Y3041. 16. Robinson PD, Shroff RC, Spencer H. Renal complications following lung and heart-lung transplantation. Pediatr Nephrol. 2013;28:375Y386. 17. Fryer JP, Benedetti E, Gillingham K, et al. Steroid-related complications in pediatric kidney transplant recipients in the cyclosporine era. Transplant Proc. 1994;26:91Y92. 18. Fonseca-Aten M, Michaels MG. Infections in pediatric solid organ transplant recipients. Semin Pediatr Surg. 2006;15:153Y161.
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