Nail abnormalities in upper extremity transplantation: Perspectives and insights from systemic diseases and organ transplantation

Abstract

Nail changes following upper extremity transplantation (UET) cannot be overlooked as they possess diagnostic and prognostic relevance in allotransplantation of upper limbs. This comprehensive review explores nail and nail bed related changes encountered in UET recipients in the literature. The differential diagnosis of nail abnormalities in UET includes a wide range of systemic, local and iatrogenic conditions other than immune responses to the allograft. It requires interdisciplinary evaluation by primary transplant surgeons, pathologists, dermatologists and immunologists. The possible underlying mechanisms of nail pathology in UET and the management are discussed. It also underscores the importance of onychodystrophy and need for timely intervention and to improve outcomes in UET recipients.

Key Words: Vascularized composite allotransplantation; Upper extremity transplantation; Hand transplantation; Nail abnormalities; Onychodystrophy; Graft rejection; Nailfold capillaroscopy

Core Tip: Nail changes after upper extremity transplantation (UET) are often overlooked but may represent early and atypical signs of graft rejection. This review synthesizes evidence from vascularized composite allotransplantation, systemic diseases, and solid organ transplantation, highlighting the diagnostic and prognostic value of nail abnormalities. By recognizing patterns such as onychomadesis, dystrophy, and nailfold capillary changes, clinicians can improve surveillance and timely intervention, ultimately enhancing long-term outcomes in UET recipients.

INTRODUCTION

Vascularized composite allotransplantation (VCA) has revolutionized the management of complex tissue defects in select patients without conventional options for reconstruction[1-4]. Unlike solid organ transplants, which involve the transplantation of a single, functionally specialized tissue type, VCA involves the transplantation of multiple, heterogeneous tissue types working together as a single functional unit. VCA procedures, such as transplants of the extremities, face, abdominal wall, and penis, involve various tissues, including skin, muscles, nerves, bones, tendons, ligaments, lymph nodes, and blood vessels[5]. The most commonly performed VCA is upper extremity transplantation (UET) for upper limb amputees. Limb allografts are unique and differ from other VCA, as they include specialized structures such as palmar skin and nails. Although often overlooked in the context of hand transplantation, and VCA in general, nail abnormalities may serve as vital indicators of immunologic status as well as underlying systemic health of patients. Changes in the nail unit may offer crucial insights into the alloimmune response affecting the hand allograft. Graft rejection may manifest atypically in the nail and adjacent soft tissue areas with various changes, underscoring the importance of surveillance and timely intervention. Monitoring the fingertips, including the nails, is therefore significant in the long-term management of UET patients.

This paper seeks to provide a comprehensive overview of nail abnormalities within the realm of UET, drawing parallels with manifestations observed in systemic diseases and solid organ transplantation (SOT). By integrating perspectives from these related fields, we aim to elucidate the mechanisms that underlie nail pathologies in UET, identify predictive correlates between onychodystrophy and allograft outcomes, and propose strategies for diagnosis and management.

This review is the first to systematically synthesize evidence on nail abnormalities in UET, highlighting their potential as early biomarkers of allograft rejection. By integrating lessons from systemic diseases and SOT, we underscore the unique diagnostic role of nails and propose an evidence-based diagnostic algorithm specific to VCA, addressing a critical gap in the literature.

LITERATURE REVIEWS

This article was designed as a narrative review synthesizing and appraising the available literature on nail abnormalities in VCA, with comparative insights from SOT and systemic diseases.

A comprehensive search of PubMed, EMBASE, and Scopus was conducted, covering publications from the introduction of modern clinical VCA in the late 1990s – marked by the first-hand transplant in 1998 – through January 2025. Search terms included individual and combined keywords such as “nail pathology”, “onychodystrophy”, “onychomadesis”, “onycholysis”, “onychomycosis”, “leukonychia”, “Beau’s lines”, “chromonychia”, “lunula”, “nailfold capillaroscopy”, “upper extremity transplantation”, “hand transplantation”, “vascularized composite allotransplantation”, “solid organ transplantation”, “rejection”, “immunosuppression”, “biomarkers”, and “dermoscopy”. These terms were searched both separately and in various Boolean combinations.

The search yielded 480 records. After automatic and manual deduplication, 347 unique records remained. Title and abstract screening excluded 260 records, leaving 140 for full-text review. Of these, 46 were excluded (e.g., non-English language, non-clinical/translational focus, or insufficient detail), resulting in 92 studies included in this review.

Studies were eligible for inclusion if they reported nail-related findings in VCA, other SOTs, or systemic/autoimmune conditions relevant to graft monitoring and immunosuppression. Both clinical outcomes (case reports, case series, reviews, and cohort studies) and translational/experimental findings were considered. Publications not in English or without clinical/translational relevance were excluded.

Findings were synthesized narratively with attention to (1) Nail abnormalities in UET and their potential association with rejection; (2) Comparative nail pathology in SOT; (3) Systemic disease-related nail findings as analogs for transplant pathology; and (4) Implications for diagnosis, monitoring, and future perspectives.

ANATOMY AND PHYSIOLOGY OF NAILS

Understanding nail anatomy is essential for correlating clinical findings with underlying pathology. The nail unit consists of the nail plate and surrounding periungual tissue over the distal phalanx. The nail plate, a keratinized laminated structure, originates predominantly from the nail bed (approximately 85%) and proximally from the matrix (approximately 15%). Its distal attachment to the skin forms the onychodermal band, while the free edge corresponds to the hyponychium[6]. Adherent material on the ventral surface increases plate density and thickness as it grows distally[7]. Normal curvature along the transverse and longitudinal axes provides stability, and the plate’s longitudinal ridges reflect those of the bed. The plate is bordered by the proximal and lateral folds; the latter cushions the nail margin, where tissue loss may lead to onycholysis and excess bulk to ingrown nails[8].

The proximal nail fold covers and protects the nail matrix and melanocytes. The eponychium (cuticle), an epidermal extension of this fold, adheres to the nail plate and together with the fold forms a dual seal against external irritants[9]. Inflammation here can produce transverse grooves known as Beau’s lines[10], localized or systemic depending on etiology. Chronic inflammation may create multiple grooves, and early cuticle loss is often a sign of chronic paronychia.

The nail matrix (15%-25%) and nail bed (75%-85%) underlie the plate. The visible portion of the matrix is the lunula, most evident on the thumb. Matrix injury can permanently impair nail formation[11]. The nail bed normally lacks a granular layer because the nail plate functions as a protective epithelium. In onycholysis, keratinization and granular layer formation occur as the plate separates from the bed.

Digital blood supply derives from an anastomotic network of the ulnar and radial arteries via the palmar arches. Each digit has four arteries, with palmar branches being dominant. The dorsal nail fold arch, distal to the interphalangeal joint, nourishes the fold and matrix through tortuous branches. The subungual region receives blood from proximal and distal arcades formed by this dorsal arch and the palmar system. Venous return parallels arterial supply. The nailfold capillary network, visible on dermoscopy, has diagnostic value[12].

NAIL CHANGES IN UET

UETs, such as hand, forearm, or above-elbow transplants, involve allografts that include the nail unit, a specialized epithelial appendage susceptible to graft rejection. The classical pattern of rejection usually involves the skin of the allograft but spares palmar skin and nails. However, rejection with nail abnormalities, occurring during the rejection process, was initially considered an atypical presentation. With increasing experience and available reports in the literature on UETs, nail pathology is no longer considered an atypical presentation. A review of the literature shows relatively few reports on nail changes in UET patients. With more than 200 UETs performed worldwide, existing reports on nail abnormalities are mostly limited to a few case reports. The commonly reported nail abnormalities after UET include onychomadesis, nail dystrophy, thinning/thickening of the nail plate, cuticular microhemorrhages, discoloration of the nail bed, and lunular alterations. Most of these nail pathology in UET recipients have been reported in association with acute rejection. Those changes may impact the aesthetics and functionality of the nails, potentially affecting the recipient's quality of life. The commonly reported nail abnormalities in UET recipients with chronic rejection include thinning of the nail and separation of the nail from the nail bed, leading to complete loss of the nail.

A unique pattern of rejection, involving a desquamative palmar rash with associated nail pathology such as dystrophy, degeneration, and thinning, was reported in four patients after UET[13]. This was characterized by nail plate weakening, with distinctive histopathologic features like parakeratosis and spongiosis, which differed from classical rejection. Patients also presented with swelling of the fingers, a desquamative rash on the palms, and symptoms such as dry skin, red papules, scaling, and lichenification. Notably, this type of rejection demonstrated resistance to conventional steroid treatment, suggesting a need for alternative therapies. Additionally, three other patients experienced onychomadesis at months 27 and 43 post-transplantation, presenting with nail dystrophy, degeneration, or complete loss. Although the nails eventually regrew, they remained soft and dystrophic in the long term[13]. Interestingly, while erythematous lesions in other areas of the body, such as the forearm and dorsum of the hand, generally resolved spontaneously or with conventional treatments, lesions on the palms and those involving the nails showed a greater resistance to therapy. Microscopic analysis of biopsies from both the palmar skin and nail beds revealed lymphocytic infiltrates, which started in the perivascular and perineural areas and advanced into the superficial dermis, leading to basal-cell epidermal liquefaction. Importantly, the same lymphocytic infiltrate was observed in the nail bed biopsies, highlighting the specific involvement of the nails in this atypical rejection pattern[14]. The findings suggest that these manifestations may be more complex than typical rejection responses, warranting further investigation into their underlying mechanisms. While the small number of patients reported complicates broad conclusions, the distinctive nature of this rejection response, particularly with nail involvement, underscores the need for vigilant monitoring and targeted interventions. This atypical pattern may reflect differences in the alloimmune mechanisms affecting integumentary tissue, potentially offering prognostic insight into the patient's response to therapy. However, it remains important to continue exploring the relationship between nail pathology and long-term outcomes, as these may provide critical information for patient management in VCA.

Apart from environmental exposure, the palmar aspect of the hands also faces persistent and repetitive mechanical stress. These effects have been shown to trigger rejection with notable changes in the nails, including dystrophy, deformation, or loss, accompanied by a desquamative rash, dry skin, red papules, scaling, and lichenification localized to the palm. Histological analysis of the affected skin and nail bed revealed features reminiscent of classic rejection, characterized by a predominance of T cells and a small number of B cells. Notably, this atypical skin rejection, marked by significant nail alterations, exhibited prolonged persistence over weeks to months and displayed limited responsiveness to steroid treatment[15].

A retrospective review of 15 hand allotransplantations in China showed nail abnormalities (uneven nails) in 12 allografts, with limited details on the timing and appearance of these nail pathology[16]. Among those patients, graft failure occurred in seven transplants, with a mean follow-up of 52 months, due to rejection and non-compliance with immunosuppressive therapy.

Although nail pathology has been reported in transplant scenario across SOT and VCA, rejection should be ruled out in the setting of nail abnormalities in the hand allograft as experienced by the authors (Figure 1). The normal microarchitecture of the nail apparatus is shown in Figure 1A. The first female military VCA patient transplanted at San Antonio Military Medical Center on February 17, 2010, underwent 13 episodes of moderate to severe acute cellular rejection over 10 years, after which the severity of rejection necessitated elective amputation on January 20, 2020[17]. Figure 1B shows a cross section of the nail apparatus from this patient, which shows intense inflammation of the nail bed/matrix and marked T cell infiltration in the perivascular zones of the proximal nail fold. One of the Pittsburgh VCA recipients developed proximal onychodystrophy, characterized by thin, uneven, and ragged nail plates without cuticle loss three years after UET (Figure 1C).

Figure 1 Comparative histopathologic findings of the normal nail and nail in chronic rejection of a hand transplant. A: The left panel shows the histology of a normal nail, highlighting the key structures such as the nail plate, distal phalanx, proximal nail fold, and nail matrix, all of which appear well-organized and devoid of any pathological infiltrates; B: The middle panel depicts the histopathologic changes seen in chronic rejection of a hand transplant. The most notable features include intense nail bed inflammation and significant perivascular infiltrates within the thickened proximal nail fold. These changes contrast sharply with the normal histology, indicating the presence of an active immune response against the transplanted tissue; C: It shows proximal onychodystrophy with thin, uneven, and ragged nail plates without cuticle loss three years after upper extremity transplantation in a vascularized composite allotransplantation recipient.

A case report details late nail lesions in a stable and compliant bilateral forearm allograft patient, occurring 60 months post transplantation. This patient experienced repeated rejection episodes, and despite appropriate immunosuppressive interventions, including lymphocyte-depleting therapy, the rejection signs persisted, ultimately resulting in the loss of nails[18]. This patient developed psoriasiform lesions on the palms, along with dystrophic nails and onychomadesis. The nails, after their initial dystrophic regrowth, were completely lost 68 months after surgery.

A review of the French UET experience recipients reports nail pathology in eight UET patients over a mean follow-up period of 9.75 years[19]. Nail abnormalities including onychomadesis, altered nail plate thickness, discoloration of the nail bed, nail ridging, trachyonychia, brittle nails, and changes in the appearance of the lunula, were observed in these patients[19]. Onychomadesis was considered as a significant finding and often occurred as an initial sign of graft rejection. This study highlighted the importance of monitoring nail abnormalities as potential indicators of graft health in UET[19].

A recent study compared nailfold capillary patterns in transplanted hands to those in the contralateral non-grafted hands of extremity transplant recipients, as well as in the hands of kidney transplant recipients (KTR). The study included six UET recipients, an age-matched and sex-matched group of 12 KTR, and 12 healthy volunteers. Nailfold video capillaroscopy revealed significant abnormalities in the hand allografts, including capillary disorganization and microhemorrhages. Surprisingly, similar, though less pronounced, changes were observed in the nailfolds of the healthy hands of extremity transplant recipients. In contrast, KTR showed normal capillaroscopic patterns. Additionally, serum concentrations of vascular endothelial growth factor (VEGF) correlated with average capillary diameter in capillaroscopy. The findings suggest advanced microvascular abnormalities in the nailfold capillaroscopic pattern of both transplanted and native extremities in hand transplant recipients, associated with elevated levels of VEGF[20].

A long-term follow-up study from Austria involving five UET recipients transplanted between 2000 and 2014 reports that two patients exhibited nail pathology along with associated skin alterations in color, texture, and vascularization[21]. As of 2020, the first patient, transplanted 17 years earlier, had experienced abnormal nail growth for the past 13 years, while the second patient, transplanted 14 years earlier, had shown diminished nail growth for the past seven years, first noticed eight years after transplantation. These nail abnormalities, which significantly impacted the patients' quality of life, may be indicative of an early stage of chronic rejection[21].

Extremity ischemia secondary to graft vascular disease due to chronic rejection can lead to various nail pathology in VCA, which may serve as clinical indicators of underlying vascular compromise. Early in ischemia, nails may exhibit pallor with a gradual onset of leukonychia due to alterations in the nail's keratin composition[22,23]. Transverse depressions across the nails (Beau's Lines) indicate interruption of nail matrix production due to ischemic stress.

NAIL CHANGES IN SOT

Patients with SOT, including those who have undergone renal and liver transplants, can experience nail changes similar to those seen in UET recipients. Common changes reported in these patients include the absence of lunulae, leukonychia, clubbing, dystrophic and brittle nails, onychorrhexis, onycholyis, onychomycosis, Muehrcke lines, and longitudinal ridging. These changes may also be related to kidney failure secondary to graft rejection post-renal transplant. In hematopoietic stem cell transplant patients, the commonly reported onychodystrophy are mostly limited to leukonychia and often resemble changes seen in systemic sclerosis and chronic graft-versus-host disease (cGVHD).

Nail changes in kidney transplant patients

In a study of nail issues encountered by hemodialysis patients and recipients of renal transplants, Saray et al[24] explored nail pathology and investigated prevalence rates, as well as explore correlations with hemodialysis and transplantation. The study included 182 hemodialysis patients, 205 renal transplant recipients, and 143 healthy individuals. Results showed elevated rates of nail disorders in both patient groups, with 69.8% of hemodialysis and 56.6% of renal transplant recipients experiencing at least one pathology. Specific nail conditions, including the absence of lunula, splinter hemorrhages, and half-and-half nails, were more common in hemodialysis patients. Leukonychia increased significantly after renal transplantation. The findings highlight the impact of renal function treatments on nail pathologies, with transplantation reducing certain onychodystrophy but leading to an increase in leukonychia[24].

In another study, KTR demonstrated higher prevalence rates of onychomycosis, Muehrcke's nail, and leuconychia compared to healthy controls. Absent lunula was a frequent finding in both KTR and controls[25]. These findings underscore the significance of nail pathology in the context of transplantation, with specific alterations observed in UET and renal transplant recipients, emphasizing the need for attention to nail health in transplant care.

Nail changes in liver transplant patients

Marinho and Perdigoto[26] reported a case of a 45-year-old woman with primary biliary cirrhosis and severe itching. The patient had a bluish-yellow color and longitudinal striations in the nail of the right index finger, a result of incessant scratching for several years. After undergoing a liver transplant, the patient regained consciousness without pruritus complaints. Remarkably, three months later, the dystrophic alterations in the nail were no longer visible, highlighting the positive impact of liver transplantation on the patient's nail condition and pruritus relief[26].

Gandhi et al[27] reported the case of a 6-year-old girl who underwent a liver transplant after failed Kasai's surgery for biliary atresia. Before the transplant, she had severe onychodystrophy, including white, dystrophic, brittle nails with onycholysis, clubbing, and watch-glass deformities. Following the transplantation, her nails significantly improved, demonstrating a near-normal appearance within five months. This case contributes to the limited literature on the positive impact of liver transplantation on reversing nail changes[27].

Shrimal and Gupte[28] reported onychodystrophy in patients with liver cirrhosis, including Terry's nails, leukonychia, dystrophic nails, onychorrhexis, onycholysis, and clubbing. Reversal of these changes post-liver transplantation has been observed in both pediatric and adult patients. In one case, a 56-year-old man with autoimmune hepatitis showed white, dystrophic nails with longitudinal ridges before transplantation. Two months post-transplantation, new normal growing nails were observed adjacent to the nail bed, highlighting the reversal of cirrhosis-related nail pathology. Additionally, a 9-month-old child with secondary biliary cirrhosis exhibited similar onychodystrophy, showing early reversal after liver transplantation at 6 weeks. These cases provide insights into the dynamics of nail abnormalities following liver transplantation[28].

Sarac et al[29] conducted a study on dermatologic manifestations in liver transplant recipients, revealing that 33.4% of patients experienced pathological onychodystrophy. The most common nail lesions included vertical streaks (14.6%), leukonychia (8.8%), and Terry's nail (1.2%). Interestingly, Terry's nails persisted even after transplantation. The study provides valuable insights into the dermatological aspects of liver transplant recipients, emphasizing the prevalence and persistence of specific nail pathology[29].

All in all, these instances demonstrate the beneficial effects of liver transplantation in reversing nail alterations and improving related symptoms such as pruritus. The observations contribute valuable insights into the evolving dynamics of nail alterations post liver transplantation, adding to the limited yet significant literature on these positive outcomes. This highlights the comprehensive advantages of liver transplantation, addressing not only the underlying liver conditions but also improving dermatological manifestations, specifically nail abnormalities.

Nail changes in hematopoietic stem cell transplantation patients

Barete et al[30] demonstrated “white nails” in 8 out of his 23 patients (38%) after autologous hematopoietic stem cell transplantation (HSCT). Miniati et al[31] examined the impact of autologous HSCT on nail microvasculature in severe diffuse cutaneous systemic sclerosis (dcSSc). Nailfold videocapillaroscopy (NVC) revealed a transition from a "late" to an "active" pattern in HSCT-treated patients, indicating improved vascular health characterized by increased giant capillaries, absence of avascular areas, and angiogenesis. This study highlights the potential benefit of HSCT in enhancing nail microvascular remodeling in severe dcSSc[31]. Huang et al[32] conducted a study on pediatric HSCT recipients, revealing that 6% of patients developed nail pathology post-HSCT, all of whom had cGVHD. The findings emphasize the association between cGVHD and nonmalignant late cutaneous changes in pediatric HSCT recipients, including nail alterations[32]. Szlauer-Stefańska et al[33] discussed nail abnormalities following allogeneic HSCT, commonly linked to cGvHD. They emphasized the importance of dermoscopic images in depicting potential non-infectious nail abnormalities, highlighting the significance of routine nail examination in clinical assessments for early detection of cGvHD manifestations[33]. Boonstra et al[34] explored the influence of HSCT on nailfold microvascular changes in severe systemic sclerosis (SSc) patients. Notably, HSCT-treated patients exhibited significant improvement in nailfold microangiopathy, particularly in capillary loss and disorganization, compared to those receiving conventional immunosuppressive therapy[34].

To facilitate comparison across transplant types and systemic diseases, we have summarized the reported nail abnormalities in a dedicated comparative table (Table 1)[11,13,19,21,22,25-28,33,35-46]. This table highlights overlapping and distinct features among UET, SOT, and systemic disorders, complementing the narrative synthesis provided in the text.

Table 1 Comparative summary of nail changes in upper extremity transplantation, solid organ transplantation, and systemic/autoimmune diseases.

Nail change	UET	Solid organ transplantation (kidney, liver, HSCT)	Systemic/autoimmune diseases	Ref.
Onychomadesis	Often with acute/chronic rejection; may precede skin changes	MMF-associated; reported after kidney/Liver transplantation	Autoimmune disease (e.g., pemphigus), viral infections (e.g., hand foot and mouth disease)	Schneeberger et al[13], Kanitakis et al[19], Hardin and Haber[35], Rault[42]
Onycholysis	May occur with rejection or chronic vascular compromise	Reported after liver transplantation; MMF-related	Thyroid disease, irondeficiency anemia, allergic contact dermatitis	Schneeberger et al[13], Cabanillas et al[22], Alessandrini et al[43]
Nail dystrophy	Atypical skin/nail rejection pattern in UET	Reported in liver transplant cases	Iron or biotin deficiency	Schneeberger et al[13], Abdelaziz et al[25], Shrimal and Gupte[28], Stefańska et al[33]
Thinning/thickening of nail plate	Seen with chronic rejection and ischemia	-	Psoriasis, systemic sclerosis	Hautz et al[21], Abdelaziz et al[25], Shrimal and Gupte[28]
Lunula changes	Changes reported around rejection episodes	Absent/reduced lunula reported in kidney/Liver recipients	Systemic sclerosis, dermatomyositis	Marinho and Perdigoto[26], Gandhi et al[27], Shrimal and Gupte[28]
Leukonychia	Described in UET recipients	Common in kidney and liver transplant; drugrelated (sirolimus/MMF)	Hypoalbuminemia, malnutrition	Marinho and Perdigoto[26], Gandhi et al[27], Shrimal and Gupte[28]
Onychomycosis	Opportunistic infection under immunosuppression	Common in kidney transplant; immunosuppressantrelated	-	Bodman et al[36], Hay and Baran[37], Mehta et al[38], Piraccini and Alessandrini[39], Zaraa et al[40], Pharaon et al[44], Lee and Lipner[45], Gaurav et al[46]
Beau’s lines	Matrix interruption from ischemia/rejection	Reported in kidney/Liver transplant recipients	Autoimmune/systemic illness, nutritional deficiencies	De Berker[10]
Trachyonychia/Longitudinal ridging	Chronic rejection; microvascular changes	Reported after HSCT	Psoriasis, lichen planus	Kanitakis et al[19], Stefańska et al[33]
Splinter hemorrhages	-	Observed in transplant recipients; drug-related	Endocarditis, vitamin C deficiency, systemic sclerosis	Saladi et al[41]
Clubbing	-	Reported especially in pediatric liver transplantation	Pulmonary and cardiac disease, systemic sclerosis	Abdelaziz et al[25], Shrimal and Gupte[28]

It summarizes the spectrum of nail changes observed in upper extremity transplantation (UET), compared with solid organ transplantation (SOT) and systemic/autoimmune diseases. While certain findings such as onychomadesis and lunula changes may herald graft rejection in UET, others (e.g., leukonychia, clubbing) are more common in SOT or systemic disease contexts. Recognizing these patterns can help differentiate immunemediated rejection from comorbid conditions and treatmentrelated effects. HSCT: Hematopoietic stem cell transplantation; MMF: Mycophenolate mofetil; UET: Upper extremity transplantation.

DIFFERENTIAL DIAGNOSIS OF NAIL CHANGES

Several autoimmune and systemic diseases like SSc, psoriasis, and dermatomyositis (DM) can cause alterations in nails that can be similar to the aforementioned nail pathology in VCA patients. Therefore, it is important to get a thorough medical and family history of the patients to eliminate false positives.

McBride and Sontheimer[47] demonstrated the significance of cutaneous signs in autoimmune diseases, particularly in SSc and DM. During the acute phase of disease activity, characteristic nailfold findings include dilated capillaries, microhemorrhages, and cuticular/eponychial hemosiderin-containing deposits (CEHD). The study aimed to distinguish between proximal microhemorrhage events and distal CEHD, conducting a Prussian blue staining experiment in vivo to validate the hemosiderin content. The case presented supported a diagnosis of amyopathic DM based on CEHD presence. These deposits, visualized with a portable dermatoscope and compact digital camera, serve as indicators of active autoimmune disease, particularly in SSc and DM, reflecting the inflammatory phase of microvascular injury. The Maricq sign, defined as a nailfold microhemorrhage that appears as distal CEHD, has been associated with systemic autoimmune diseases, including DM and systemic sclerosis[19,47].

Fallahian et al[48] reported a case of eponychial fold lesions in a patient with redness indicating an underlying human papillomavirus positive wart following successful bilateral UET.

Hardin and Haber[35] demonstrated that onychomadesis, characterized by the separation of the proximal nail plate from the nail bed, has associations with autoimmune disease, major medical illness, neonatal illness, medications, and infection. The literature review from January 1960 to March 2013 revealed common associations such as pemphigus vulgaris, hand-foot-mouth disease, retinoids, lead, lithium, chemotherapy, and antiepileptic medications[16,19,35].

Singal and Arora[23] investigated the associations of nail abnormalities specific to various organ systems in the body. The most common nail changes associated with these included longitudinal bands, splinter hemorrhages, koilonychias, leukonychia, dystrophic nails, brittle nails, terry’s lines, beau’s lines, and Muehrcke’s lines. These changes pertain to regular organ system diseases involving heart, lungs, vascular system, gastrointestinal tract and brain. Onychotillomania and striated leukonychia are specific to psychological disease, whereas autoimmune diseases like systemic lupus erythematosus, systemic sclerosis, rheumatoid arthritis present with nail manifestations like beau’s lines, periungual telangiectasias, splinter hemorrhages, ragged cuticle and pitted scars[23].

Onychodystrophy initially presenting with a clinical aspect suspicious of proximal subungual onychomycosis[19] have been described[36-40], a recently recognized form of onychomycosis that primarily affects immunosuppressed patients.

One of the most common systemic causes of nail abnormalities is systemic sclerosis. NVC plays a crucial role in SSc[49-53], aiding in early diagnosis and monitoring microvascular abnormalities. SSc microangiopathy evolves through distinct NVC patterns (early, active, and late), providing insights into disease progression. These patterns correlate with clinical measures, autoantibodies, and subsets of cutaneous involvement. The presence of giant capillaries and hemorrhages indicates early SSc, while capillary loss, disorganization, and ramified capillaries signify advanced stages. Higher endothelin-1 levels are associated with late microangiopathy, emphasizing its role in disease progression[54]. NVC patterns aid in differential diagnosis and reflect the evolution of SSc microvascular damage[44,55].

In sclerodermatous cGVHD, resembling SSc, nailfold capillary abnormalities differ from those in SSc, highlighting distinctive microvascular features. NVC in sclerodermatous cGVHD patients does not exhibit the severe capillary abnormalities seen in SSc, indicating a lack of contribution to the pathophysiology of cGVHD[56,57]. Additionally, a case study reveals lichenoid graft-versus-host disease (GVHD) involvement in oral and nail pathology, showcasing the complexity of nail alterations in the context of GVHD[58]. Despite distinct nailfold capillary patterns observed in sclerodermoid GVHD after allogeneic HSCT, these patterns do not correlate significantly with specific clinical symptoms of the disease.

Muddasani et al[59] explored chromonychia, abnormal nail discoloration, involving the matrix, bed, or plate. Colors indicate specific associations: (1) Blue (Wilson disease, silver ingestion); (2) Brown/black (melanonychia); (3) Erythronychia (neoplasm or systemic conditions); (4) Orange-brown (iron exposure); (5) Yellow-brown (nicotine use); and (6) Yellow (yellow nail syndrome, environmental exposures). Blue discoloration may be focal or diffuse, seen in Wilson disease, argyria, and pernicious anemia[60,61]. Melanonychia may result from melanocytic neoplasms or fungal infections[62,63]. Erythronychia presents as a pink-red vertical column, while rubronychia involves red discoloration of the entire nail[64]. Yellow chromonychia is linked to yellow nail syndrome and environmental exposures[65].

They also discussed physical signs of nail bed disease as potential indicators of nutritional imbalances. Splinter hemorrhages, caused by red blood cell extravasation, can result from trauma, subacute bacterial endocarditis, scurvy, or hemochromatosis[41]. Leukonychia, white nail discoloration, can be true (persistent) or apparent (disappearing with pressure), seen in conditions like Muehrcke lines, Terry nails (linked to chronic liver disease), and Lindsay nails (associated with chronic kidney disease). Muehrcke lines are transverse white bands related to hypoalbuminemia, malnutrition, and acrodermatitis enteropathica[66]. Terry nails involve leukonychia covering over 50% of the nail and are linked to chronic liver disease[67], while Lindsay nails cover 50% or less and are associated with chronic kidney disease[66]. Onycholysis, the separation of the nail plate from the bed, can be caused by various factors, including thyroid disease, trauma, allergic contact dermatitis, iron-deficiency anemia, pellagra, and Cronkhite-Canada syndrome[59].

Muddasani et al[59] also reviewed various pathological changes in the nail plate associated with nutritional imbalances. Examples of observed nail plate changes include transverse leukonychia, characterized by opaque white bands in the same position in multiple nails, and linked to conditions like acrodermatitis enteropathica, pellagra, hypocalcemia, and hemochromatosis. Mees lines, transverse opaque white bands, were associated with arsenic poisoning[59]. Clubbing, indicated by a Lovibond angle exceeding 180°, was linked to conditions such as citrullinemia, hypervitaminosis A, congenital hypothyroidism, and poisoning from various substances. Koilonychia, involving spoon-shaped nail plates, was associated with trauma, iron-deficiency anemia, gastrectomy, Plummer-Vinson syndrome, riboflavin deficiency, pellagra, and vitamin C deficiency. Onychomadesis, complete onycholysis beginning at the proximal nail plate, was associated with trauma, chemotherapy, lead poisoning, autoimmune disease, coxsackievirus, and hypocalcemia. Beau lines, transverse grooves or depressions in the nail plate, were linked to protein deficiency, pellagra, hypocalcemia, chronic alcoholism, and arsenic toxicity. Onychorrhexis, longitudinal ridging, was associated with aging, rheumatoid arthritis, iron-deficiency anemia, arsenic poisoning, zinc deficiency, and brittle nail syndrome. Trachonychia, characterized by longitudinal ridging and a sandpaper-like surface, was associated with factors like aging, wet work, dehydrating agents, and poor nutrition. Brittle nails, defined by a thin and brittle nail plate, were associated with factors like aging, wet work, dehydrating agents, poor nutrition, and kwashiorkor[59].

Lichen planus is a chronic inflammatory disorder that can lead to significant onychodystrophy resembling hand rejection in VCA. Nail pathology in lichen planus often presents as longitudinal ridging, onychorrhexis, thinning, and splitting of the nail plate[68,69]. Severe cases may show pterygium formation, where scarring leads to permanent nail loss, mimicking the dystrophic changes observed in hand rejection. The inflammatory destruction of the nail matrix in lichen planus, driven by T-cell-mediated autoimmune responses, closely mirrors immune-mediated injury seen during acute rejection episodes in VCA. Nailfold capillary changes and periungual inflammation observed in lichen planus can further complicate the differentiation between rejection and autoimmune processes, necessitating histopathological correlation for accurate diagnosis in VCA recipients.

Psoriasis, a chronic immune-mediated skin disorder, frequently affects the nails and can lead to onychodystrophy that mimics hand rejection in VCA. Nail psoriasis commonly presents as pitting, onycholysis, subungual hyperkeratosis, and oil-drop discoloration, which can resemble the ridging, discoloration, and structural deformities seen in rejection[70,71]. The underlying pathophysiology involves hyperproliferation of keratinocytes and T-cell-driven inflammation, leading to nail matrix and bed alterations. In VCA patients, distinguishing psoriatic nail pathology from rejection is critical, as both conditions may exhibit periungual erythema and nail bed changes. Dermoscopic examination and histopathology, including the absence of lymphocytic infiltrates characteristic of rejection, can aid in differentiation.

THE ROLE OF IMMUNOSUPPRESSIVE MEDICATIONS IN NAIL CHANGES

The nail abnormalities observed in transplant recipients, other than UET, indicate that immunosuppresants have direct and indirect effect on the nails of these patients. Standard immunosuppressive drugs such as rapamycin, sirolimus, mycophenolate mofetil (MMF), have deleterious effects on the nail unit, aside from protecting the allograft from immune responses[25,72]. These drugs have been linked to post-transplant nail changes. The various changes include leukonychia, slow growth, onychomalacia, onychorrexis, onycholysis, splinter hemorrhages, pyogenic granulomas, and photo-onycholysis[19,73]. Monitoring and understanding these drug-induced onychodystrophy are crucial in transplant care[73].

Since the UET includes the nail, the immune responses exerted on it can be used as an indicator for monitoring the allograft. Nail abnormalities can be caused by graft-versus-host reactions, surgical methods, and tissue quality[74]. The effect of global immunosuppression makes patients more susceptible to infections, especially bacterial nail bed infections or fungal nail infections (onychomycosis)[36,75-77]. These infections can lead to nail discoloration, thickening, or even loss[36]. Immunosuppressive medications can also affect the nail bed vascularization, which in turn influences nail growth[78].

A study by Mahé et al[73] focused on renal transplant recipients receiving sirolimus. Among 80 patients, 74% reported nail alterations[73]. The predominant changes were slow nail growth, onychomalacia, onychorrexis, and leukonychia. Additionally, onycholysis, erythema, splinter hemorrhages, and pyogenic granulomas were also noted. The inhibition of the epidermal growth factor pathway by sirolimus is the mechanism implicated on these nail pathology.

The use of MMF has been associated with onychodystrophy such as premature separation of the nail plate, causing onycholysis, loose toenails, and nail loss in organ transplant recipients[42,79]. Rault[42] reported a renal transplant patient experiencing blisters, loose toenails, and nail loss due to MMF usage. Discontinuation improved symptoms, but reinitiating MMF led to recurring issues, even with lower dosages. Feng et al[79] reported the first case of mycophenolic acid (MPA)-induced onychomadesis, emphasizing the rarity of nail disorders as adverse effects of MPA despite its wide use in rheumatic diseases and organ transplantation[79]. These drugs are also responsible for some other common nail abnormalities such as leukonychia, longitudinal ridging, and absence of lunula. However, these nail pathologies are very common in the general population as well, making it challenging to ascertain the specific role of transplantation and/or immunosuppressive treatment in their occurrence[13,18,19].

CLINICAL ASSESSMENT, DIAGNOSIS AND MONITORING OF NAIL CHANGES

A comprehensive clinical examination of the nails must include assessment of anomalies such as variations in thickness, color, texture, or shape, as it enables prompt observation of any noticeable changes and provides insightful data regarding the overall condition of the nails[43]. Furthermore, abnormalities in the nails may be significant clinical indicators of underlying immune responses and side effects from immunosuppressive drugs. Early detection of these alterations allows for rapid intervention and treatment regimen modification to mitigate any potential consequences[80].

Nail imaging also plays a prominent role in the diagnosis of onychodystrophy. To obtain detailed nail images, advanced imaging methods such as dermoscopy and high-resolution nail photography can be utilized[81]. In particular, dermoscopy provides magnified views of the nail plate, making it easier to diagnose various nail problems[81]. Furthermore, dermoscopy, also known as onychoscopy, is helpful in diagnosing various nail disorders and malignancies and contributes to the evaluation of the nail apparatus[82]. A nail biopsy, particularly with Periodic Acid-Schiff staining, may be needed in some circumstances to remove a sample of tissue from the damaged nail[83]. It is one of the simplest, safest and fastest methods for diagnosing onychomycosis, especially when routine laboratory procedures like potassium hydroxide examination and culture are nonproductive or when imaging and clinical examination fail to provide a definitive diagnosis[83,84]. Under a microscope, this sample can be examined to identify the underlying cause of nail changes. Similarly, reflectance confocal microscopy can also be used for diagnosing onychomycosis[44]. Blood tests may be performed to assess the patient's overall health and identify potential systemic factors contributing to nail pathology[45]. These tests can help rule out underlying medical conditions that may be affecting the nails.

To detect changes in nails over time, longitudinal monitoring is necessary. Clinicians can track the development of nail changes and modify patients' treatment plans as needed through regular follow-ups.

MANAGEMENT AND INTERVENTIONS

The management and interventions for nail-related issues in UET constitute essential elements of post-transplant care. The primary concern regarding onychodystrophy in UET is the potential association with allograft rejection. The diagnostic algorithm (Figure 2) provides a concise overview of the approach to a differential diagnosis in UET patients with nail abnormalities and the management approach.

Figure 2 Diagnostic algorithm for nail abnormalities in vascularized composite allotransplantation patients. The algorithm outlines a systematic approach to diagnosing and managing nail abnormalities observed in upper extremity transplantation patients. UET: Upper extremity transplantation.

In clinical practice, the diagnostic algorithm (Figure 2) can be integrated into routine follow-up visits, where transplant surgeons and dermatologists collaborate in nail surveillance. Skin biopsy remains the gold standard for confirming VCA rejection, graded using Banff criteria and supported by recent molecular data. When rejection is suspected, nail bed biopsy may provide complementary and, in some cases, earlier diagnostic information.

However, practical challenges include patient discomfort, risk of nail deformity, and the need for dermatopathology expertise. Thus, nail biopsy should be considered when skin biopsy findings are inconclusive or when nail pathology is the dominant presentation. This positioning aligns with published evidence supporting the role of standardized skin biopsy in VCA rejection monitoring[85-87] and the clinical indications, techniques, and complications of nail biopsy[83,88].

Cases accompanied by skin changes necessitate a skin biopsy for histopathological confirmation to rule out ongoing rejection. In the absence of skin changes, dermatological evaluation is required to explore local and systemic causes for nail changes. Consideration of drug-induced onychodystrophy, particularly linked to immunosuppressive drugs, is crucial when other common causes are ruled out. Functional limitations induced by nail changes are exceedingly rare; however, if present, contemplate a change in the drug regimen following a thorough assessment by an immunologist. In instances where no specific etiology can be established, the nail pathology may potentially represent normal pathophysiological alterations in the allograft due to prolonged ischemic insult before revascularization or the strain of hand overuse in the transplanted scenario[13]. The skin biopsy is regarded as the gold standard for establishing the diagnosis of VCA rejection. The Banff grading classification of acute rejection in UET is based on skin biopsies but does not include assessment of nail skin fold or nail bed changes on histopathology.

FUTURE PERSPECTIVES

Future perspectives in studying nail alterations in UET are promising, driven by emerging technologies and innovative tools. The use of imaging technologies such as high-resolution ultrasonography, optical coherence tomography, and magnetic resonance imaging, may offer precise insights into nail microstructure and blood flow dynamics. Incorporating these technologies into regular follow-ups could help in early detection and can provide noninvasive monitoring of the allograft[89,90]. Assessment of molecular markers in the nail bed scrapings and exploring targeted therapies could become valuable treatment strategies in UET. These strategies may involve utilizing targeted medications to regulate vascular responses, minimize inflammation, or promote tissue regeneration in the nail bed.

Future directions may include integrating AIassisted dermoscopy into nail monitoring workflows to detect subtle morphological changes before clinical symptoms emerge. Recent work illustrates feasibility and clinical promise in nail disorders[46,91]. In parallel, biomarkerbased approaches – such as donor-specific antibodies, VEGF, and circulating microRNAs – could be correlated longitudinally with nail abnormalities to provide noninvasive surrogates of graft immunologic status. Combining imaging and biomarkers with the proposed clinical algorithm may yield a more sensitive, multiparametric surveillance strategy in UET recipients.

CONCLUSION

Nail involvement in UET, often overlooked, can serve as indicators of alloimmune responses to the graft and overall patient well-being. A review of the limited available literature highlights the importance of monitoring these nail alterations, as they may signal graft rejection in the context of UET[92]. The diverse manifestations of nail abnormalities across various types of transplantation, including solid organ transplants, highlight the complex interplay between immune responses, vascularization, and the effects of chronic immunosuppression. The clinical significance of onychodystrophy in UET is closely linked to allograft rejection, necessitating constant surveillance by both patients and the transplant team. Advances in imaging technologies and interdisciplinary approaches are poised to enhance early detection, diagnosis, and management of nail-related issues, potentially improving long-term outcomes in UET. Ongoing research and innovation in this area hold the potential to refine transplant care, ensuring that subtle indicators like nail pathology are effectively integrated into broader monitoring strategies.