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Hand Transplantation inChildren
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ShaunD.Mendenhall, ToddJ.Levy,
SandraAmaral, BenjaminChang,
andL.ScottLevin
29
Abstract
Pediatric hand transplantation is a recent addition to the eld of vascularized composite allotransplantation. After careful patient selection,
thorough preoperative planning, and repeated
rehearsals by a large multidisciplinary team,
we recently completed the world’s rst bilateral distal forearm level hand transplant in an
eight-year-old child who was already on
S. D. Mendenhall · L. S. Levin (*)
Division of Plastic, Reconstructive, and Oral Surgery,
Division of Orthopaedic Surgery, Children’s Hospital
of Philadelphia, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA, USA
e-mail: mendenhals@chop.edu;
Scott.levin@pennmedicine.upenn.edu
T. J. Levy
Center for Rehabilitation, The Children’s Hospital of
Philadelphia, Philadelphia, PA, USA
e-mail: levyt@chop.edu
S. Amaral
Division of Nephrology, Children’s Hospital of
Philadelphia, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA, USA
e-mail: amarals@chop.edu
B. Chang
Division of Plastic, Reconstructive, and Oral Surgery,
Division of Orthopaedic Surgery, Children’s Hospital
of Philadelphia, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA, USA
Division of Plastic Surgery, Department of
Orthopaedic Surgery, Perelman School of Medicine at
the University of Pennsylvania, Philadelphia, PA, USA
e-mail: benjamin.chang@pennmedicine.upenn.edu
immunosuppression following a living donor
kidney transplant. Short-term outcomes at 30
months have been promising including return
of hand intrinsic motor function, return of sensibility of the hands, and ability to perform
self-care and age-appropriate play. The
sequelae of long-term systemic immunosuppression and incomplete nerve recovery will
continue to be a limiting factor in pediatric
hand transplantation, but with careful patient
selection, planning, and modern medical and
surgical care, hand transplantation is now an
option for children with upper limb loss.
Keywords
Hand transplantation · Hand transplant ·
Vascularized composite allotransplantation ·
Upper extremity transplant · Heterologous
hand transplant · Pediatric hand surgery ·
Hand amputation · Prosthetics
29.1 Introduction
Vascularized composite allotransplantation
(VCA) refers to the transplantation of multiple
tissue types together as a single functional unit
such as an upper extremity or face, which contain
bone, muscle, fat, vessels, nerves, and skin [1].
Beginning in 1998 with the rst successful hand
transplant in an adult [2], the modern era of VCA
has been a worldwide effort with transplants and
research taking place on nearly every continent
© Springer Nature Switzerland AG 2023
G. Pajardi (ed.), Pediatric Hand Surgery, https://doi.org/10.1007/978-3-031-30984-7_29
353
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S. D. Mendenhall et al.
of the world [3]. Since then, many major milestones have been reached in this growing eld
including the world’s rst bilateral hand transplantation in a child performed by our team at the
Children’s Hospital of Philadelphia in 2015 [4–
8]. This chapter will present the historical, ethi-
cal, psychosocial, donor, surgical, immunological,
and rehabilitation considerations of this case as
well as the outcomes at 30 months.
29.1.1 Hand andUpper Extremity
Transplantation
With approximately 150 transplants in over 100
patients worldwide, transplantation of the hand and
upper extremity has become by far the most widely
performed VCA to date [3]. The rst modern-era
hand transplant occurred in Lyon, France, when
Jean-Michel Dubernard led a team of international
surgeons in a unilateral dominant hand transplant
in 1998 [2]. Patient noncompliance with immunosuppression led to rejection of this allograft and the
subsequent need for transplant removal, but longterm success was found in the second modern-era
hand transplant four months after the rst [9]. Dr.
Warren Breidenbach and his team led this transplant in Louisville, which would become the longest VCA transplant in the world currently at nearly
25 years posttransplant. Since then, many bilateral
transplants and even above-elbow transplants have
been performed worldwide which have demonstrated technical success and excellent functional
outcomes in select patients. Patient survival has
been good with only one patient death from isolated upper extremity transplantation in the worldwide experience [10]. The ve-year allograft
survival rate for upper extremity transplants
approaches 90% [3, 11], which is better than that of
other deceased donor solid organ transplants, with
the best outcomes reported for heart transplants at a
75% ve-year survival rate [12, 13].
Functional outcomes of hand transplantation
have been promising. Nearly all hand transplant
patients recover protective sensation of the hand and
84% recover discriminative touch [14]. Motor function is more dependent on the level of the transplant
with wrist-level transplants generally obtaining the
best functional outcomes. Nevertheless, even aboveelbow transplants can regain meaningful function
[15]. Outcomes data from the International Registry
on Hand and Composite Tissue Allotransplantation
(www.handregistry.com) and others demonstrate an
overall trend toward continued functional improvement over the life of the allograft [14, 16]. Of note,
starting just one year after transplant, the Disability
of the Arm, Shoulder, and Hand (DASH) scores are
on average better for transplants than for prosthetic
users [14, 16, 17].
As with solid organ transplantation, VCA
outcomes have been tempered by the sequelae
of lifelong immunosuppression including
opportunistic bacterial, fungal, and viral infections, metabolic complications, and malignancies [18, 19]. Since these transplants are not
lifesaving but quality of life enhancing, the benets of improved function and appearance must
be carefully weighed with the complications of
immunosuppression.
29.1.2 Upper Extremity
Transplantation inChildren
Transplantation of the upper extremity in children is a very recent and limited addition to the
eld of vascularized composite allotransplantation. The rst upper extremity transplant in a
child was performed in Malaysia between two
identical twins in 2000 by Pathmanathan [20,
21]. This case consisted of an above-elbow arm
transplant for congenital absence of the hand in
one twin from the other who had a fatal meningoencephalocele. Although under reported, the
child went on to have excellent function of the
transplanted arm as of the report on her eightyear follow-up [20]. Because the donor was her
twin sister, no immunosuppression was needed.
The second attempt at a pediatric arm transplant,
and the rst allotransplant requiring immunosuppression, took place in Mexico City ten years
later. A 17-year-old female underwent bilateral
proximal arm transplantation 3 years after a highvoltage electrical injury. Unfortunately, this
patient had massive intraoperative blood loss and
resuscitation and died in the early perioperative
29 Hand Transplantation inChildren
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Fig. 29.1 Preoperative
photo of the world’s rst
bilateral hand transplant
recipient (top) and at 25
months posttransplant
(bottom). Photos
courtesy of the
Children’s Hospital of
Philadelphia
355
period of a cardiopulmonary event attributed to a
severe cytokine release syndrome associated with
thymoglobulin [10]. In 2015, our team performed
a bilateral hand transplant on an eight-year-old
quadrimembral amputee at the Children’s
Hospital of Philadelphia in the United States
(Fig. 29.1) [4–7]. This child had lost all four
limbs and his kidneys due to staphylococcal sepsis at the age of two and had previously undergone living-related donor kidney transplantation
from his mother at the age of four. The patient
continues to do well 8 years posttransplant and
has gained remarkable function of the hands. A
review of his case follows that demonstrates the
importance of careful patient selection, thorough
preoperative planning, intraoperative technical
expertise, and postoperative medical and rehabilitation care by a large multidisciplinary team.
29.2 Case Report oftheFirst
Pediatric Bilateral Hand
Transplant
Complete details of the rst bilateral hand transplantation performed on a child were previously
reported [4]. Briey, after two years of evaluation
and planning by a large multidisciplinary team
including orthopedic, plastic, and transplant surgeons, transplant immunologists, occupational
and physical therapists, social workers, pediatric
psychologists, pediatric pharmacists, and ethicists, the decision was made to proceed with
transplant. The risks of slightly increased immunosuppression over the patient’s current kidney
transplant regimen were deemed worth the benets of having arms. The Institutional Review
Board viewed the transplant as novel clinical care
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S. D. Mendenhall et al.
and considered the procedure exempt from full
review. Multiple preoperative rehearsals took
place in preparation for the surgery. After a little
over two months on the waitlist, an appropriate
donor was found and the transplant was performed in a 10 h and 40 min operation with a
large surgical team. In the early postoperative
period, one of the hands became ischemic due to
thrombosis of the ulnar artery which required
immediate take back to the OR and revision of
the anastomosis. The patient was hospitalized for
ve weeks as an inpatient and for two weeks in
inpatient rehab. By six months, the patient had
regained light touch sensation of the hands.
Around an eight-month posttransplant, the
patient had clear intrinsic muscle function return
in the right hand and by ten months in the left.
This intrinsic function was also conrmed by
functional MRI.During the rst year the patient
had multiple bouts of acute rejection treated with
a bolus of steroids and topical agents along with
an increase in maintenance immunosuppression.
As of 30-month follow-up, he has continued to
improve in sensation, motor function, and psychosocial integration of the hands and is more
independent with self-care such as eating, toileting, and clothing himself. He is also able to write
and to play sports such as baseball and football.
Serial functional brain imaging studies including
diffusion tensor imaging MRI and magnetoencephalography have demonstrated that the massive cortical reorganization associated with
amputation is reversible back to similar patterns
to the pre-amputation state after transplantation
of new hands [22].
29.2.1 Ethical Considerations
Vascularized composite allotransplantation has
had signicant ethical implications since its
inception [23–25]. Traditionally, VCA transplants have been considered nonlifesaving but
quality of life-enhancing procedures. Therefore,
one of the biggest ethical dilemmas for VCA is
weighing the risks of lifelong immunosuppression (IS) with the benets of improved function,
appearance, and independence that transplanta-
tion offers. With children, this is obviously a
bigger dilemma, since with longer exposure to
IS the risks of untoward side effects are greater.
For example, the incidence of nonmelanoma
skin cancer in the solid organ transplant patient
is approximately 50% at 20 years, demonstrating that children undergoing hand transplantation in their teens are at substantial risk for skin
cancers in early adulthood [26–28]. In addition,
other nonmelanoma skin cancers and nonskin
cancers, such as non-Hodgkin lymphoma, are
also more prevalent in pediatric solid organ
transplant recipients over time (Yanik, Francis).
In one study of pediatric kidney transplant
recipients, nearly 17% experienced a posttransplant cancer over a median follow-up of 13
years (Francis). The risk of renal failure from
calcineurin inhibitors is another important consideration and is both dose and time dependent
[29]. Children and their caregivers should
understand that there is a possibility of needing
a kidney transplant before they reach middle
age. The advantage of our patient was that he
was already on IS for a renal transplant which
made the decision easier to proceed with bilateral arm transplantation.
Some authors have recently argued that VCA
transplants are actually lifesaving, thus tipping
the risk benet ratio [30]. In this view, the concept of “social death” is introduced which
includes ostracism, social isolation and loneliness, and loss of personhood and a worthwhile
life [30]. People suffering from social death have
higher mortality rates, suicidal ideation, and
attempts. Those with severe disgurement
including amputations (especially quadrimembral amputees and facial disgurement) are at
high risk for social death and therefore can have
a lifesaving benet from VCA. The concept of
social death should be considered with screening
children for hand transplantation and other
VCAs.
Another ethical consideration for pediatric
transplantation is the likelihood of experiencing
chronic rejection leading to graft loss at some
point in the future. We are now starting to appreciate chronic rejection in vascularized composite
allotransplantation since the rst of these trans-
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357
plants is now nearing 25 years of follow-up.
Although the rst US hand transplant patient
Matthew Scott is still doing very well and has an
excellent appearance and function of his hand,
there have been reports in other patients of
changes consistent with chronic rejection including graft brosis, thinning of the skin, loss of ngernails and adnexal structures, accelerated
aging, and even graft vessel thrombosis from intimal hyperplasia leading to removal of the
allograft [31–33]. This means children receiving
VCAs will face the real threat of having to deal
with loss of the allografts in early middle age and
potentially the possibility of re-transplantation.
These possibilities should be discussed with
caregivers and included in the informed consent
process for pediatric VCA.There are many other
ethical considerations for pediatric VCA that are
beyond the scope of this chapter [23–25,
34–37].
29.2.2 Psychosocial Considerations
Psychosocial considerations are extremely
important for successful VCA transplantation in
adults and children. The worldwide experience
in adult hand transplantation has demonstrated
that one of the biggest risk factors for allograft
failure is patient noncompliance [3, 38, 39].
Experience with pediatric solid organ transplantation has demonstrated signicant problems
with patient noncompliance with IS therapy,
especially in the adolescent patient [34, 40, 41].
Strong parental and family support is associated
with better pediatric compliance and should be
an important factor in the screening process for
hand transplantation in children [42, 43]. In addition to compliance with IS, children who are
being considered for hand VCA should also have
a certain amount of maturity and determination
that will allow them to cope with the potentially
long hospital stay (seven weeks in our patient)
and the vigorous hand therapy regimen following transplantation. A psychosocial subcommittee including social workers, psychologists, and
psychiatrists should be involved in the screening
process to help determine if a candidate has the
psychological stability and resilience needed to
cope with the vigorous demands of postoperative
therapy, medical treatment, and close follow-up.
The team should be prepared to provide the pediatric recipient with increased support as he/she
transitions to adolescence and adulthood.
29.2.3 Donor Considerations
One of the biggest challenges in pediatric VCA is
nding a suitable donor. We analyzed the United
Network on Organ Sharing (UNOS) database and
found that in the United States only about 8% of
all organ donors are pediatric (ages 0–17) and
that only about 15 children per year in the entire
country would be a match for our recipient based
on blood type, age ±2 years, and ethnicity [44].
Another issue is the sensitive nature of obtaining
authorization from family members once an
appropriate donor is found. We conclude that
pediatric VCA donors are rare and may require
longer travel times for procurement. This will be
a limiting factor for pediatric VCA moving forward. In our particular case, despite the odds, an
appropriate donor was found in just over two
months after listing our patient. We did travel a
considerable distance for procurement but were
able to limit the cold ischemia time to approximately 6 h. We utilized three-dimensional printed
hand models for size comparison between our
recipient and the donor (Fig.29.2) [8].
29.2.4 Surgical Considerations
29.2.4.1 Surgical Team
There are a number of important surgical considerations in pediatric hand transplantation. It is
important to develop a surgical team familiar
with pediatric hand surgery and pediatric microsurgery. The team must dedicate themselves to
the signicant time commitment required for preoperative planning, surgical rehearsals, the
lengthy transplant operations, and as in our case
the potential for vascular compromise and urgent
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S. D. Mendenhall et al.
Fig. 29.2 Photos of three-dimensional printed hand next to donor hand for size comparison prior to procurement
reexploration in the OR.The team must be willing to be available at all times and to expeditiously return home if travelling for the moment
when an appropriate donor is found.
29.2.4.2 Procedure
The donor limbs were procured and perfused
with Belzer UW cold storage solution. Cold ischemia time was 6 h. Operating room preparation
of the recipient included bilateral upper extremity indwelling axillary nerve block catheters,
large bore lines for vascular access, and thymoglobulin and intravenous methylprednisolone
induction. Four teams worked simultaneously on
the donor and recipient limbs, identifying and
attaching sterile labels to major peripheral nerves,
Fig. 29.3 Intraoperative view of the recipient limb being
prepared for transplant by identifying and tagging all key
structures. Used with permission from Amaral S, Levin
LS.Pediatric and congenital hand transplantation. Current
opinion in organ transplantation. 2017;22(5):477-83
tendons, and vessels to facilitate repair following
bony xation (Fig. 29.3). Osteosynthesis was
done with Materialise (Leuven, Belgium) custom
cutting guides applied to the donor and recipient
radius and ulna, based on preoperative CT planning and three-dimensional printing, saving
approximately 1 h of ischemia time (Fig. 29.3)
[6]. Following rigid osteosynthesis with plates
and screws, microsurgical repair of the radial and
ulnar arteries was followed by multiple vein
repairs and reperfusion (Fig.29.4). Tenorrhaphy
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Fig. 29.4 Right hand
transplant immediately
after reperfusion
Fig. 29.5 Right hand
immediately after
transplantation surgery
359
of the exor and extensor tendons of the wrist,
thumb, and digits was then performed while
keeping the wrist in 30° of extension and the
hand in a st. This was followed by repair of the
median, supercial radial, and ulnar nerves.
Interdigitating skin aps were closed with excess
donor skin included for accommodation of swelling and subsequent biopsies (Fig.29.5).
Despite anticoagulation with heparin infusion,
2 h after the operation, the right hand was noted
to be poorly perfused (Fig. 29.6) likely due to
postoperative edema and redundancy of the ulnar
artery repair that led to kinking. This was recognized immediately, and the patient was returned
to the operating room for vascular revision, which
included shortening the ulnar artery repair and
performing an additional venous anastomosis of
a vena comitans of the ulnar artery using an arterial interpositional graft that was banked from the
donor. There were no further vascular events.
29.2.4.3 Early Postoperative
Monitoring
Posttransplantation surveillance included daily
physical examination of the limbs as well as continuous pulse oximetry to monitor tissue perfusion. Weekly skin biopsies were done and graded
by the 2008 Banff criteria [45]. The patient
received standard antimicrobial prophylaxis with
valganciclovir and trimethoprim–sulfamethoxazole. He transitioned from heparin to aspirin by
day 3 after the operation.
29.2.5 Immunological
Considerations
Postoperatively, the patient received thymoglobulin induction with intravenous methylprednisolone (10 mg/kg), mycophenolate mofetil (600
mg/m2 per dose), and tacrolimus. Goals trough
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