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Epidermolysis Bullosa

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ChiaraNovelli, ChiraraParolo, VeronicaFasoli, andGiorgioPajardi

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a congenital disease caused by a mutation in theCOL7A1gene, it causes several systemic and acral dysfunctions. The affected patients frequently show hand contractures and pseudosyndactyly. Although multiple treatments exist that can improve the hand malformations, there are currently still no radical cures for this disease because of its high recurrence rate. The surgical treatment aims to increase hand function and nally ameliorate patients’ quality of life, despite recurrence of the disease is something certain. A correct surgical procedure should always be associated with correct postoperative skin dressings and splinting. Hand function is normally substantially improved after the complete release of pseudosyndactyly and achievement of favorable digital web spaces. Recurrence takes place normally in 2–4 years, getting worsen with the increasing age of the

C. Novelli (*) · C. Parolo · V. Fasoli Milan, Italy e-mail: chiara.novelli@multimedica.it;

chiara.parolo@multimedica.it

G. Pajardi Department of Hand Surgery and Rehabilitation, S. Giuseppe Hospital IRCCS MultiMedica, Milan University, Milan, Italy e-mail: gpajardi@centrostudimano.it

patients. In conclusion, surgical correction followed by skin dressing changes is an effective approach to improving mitten-hand malformations in RDEB patients.

Keywords

Recessive dystrophic epidermolysis bullosa · Hand deformity · Surgical management · Wound dressing · Postoperative splinting

19.1 Denition andClassication

Epidermolysis bullosa (EB) is a rare genetic disorder characterized by skin fragility and susceptibility to rubbing, determining the formation of blistering and shearing lesions, spontaneously or even due to the mildest trauma, such as gentle pressure or friction. In particular, the term “Epidermolysis Bullosa” (EB) includes a heterogeneous group of hereditary diseases that can be divided into four major subtypes: EB simplex (EBS), junctional (JEB), dystrophic (DEB), and Kindler syndrome (KS).

Some of these are very slight, with a little affection of the skin that resolves spontaneously during growth; some others are very severe and can cause death during intrauterine development or neonatal age. Subtypes are determined by several factors including the level of skin cleavage, phenotype, mode of inheritance, and molecular

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origin. Generally speaking, EBS encompasses all subtypes of EB and it is characterized by mechanical fragility and blisters conned to the epidermis within the basal keratinocytes. JEB includes all subtypes with blisters formation within the lamina lucida of the skin basement membrane. DEB patients have blisters formation in the supercial papillary dermis, at the level of the anchoring brils. KS patients have blisters formation in multiple levels within or beneath the basement membrane.

In addition to the manifestations of skin and mucous membranes, EB can affect multiple body systems, causing several functional deciencies. For example, the typical hand deformities that develop in recessive DEB (RDEB), due to reduced or absent collagen VII, have a devastating impact on the quality of life of patients and include the following: adduction contracture of the thumb; pseudosyndactyly of the digits; exion contractures of the interphalangeal (IP), metacarpophalangeal (MCP), and wrist joints; less frequently, extension contractures of the MCP joints from dorsal scarring. The “mitten” deformity develops when the hand becomes encased in an epidermal cocoon. All structures in the hand may be affected: cutaneous involvement results in dermal brosis, pseudosyndactyly, contractures, atrophic nger and thumb tips, nail loss (due to subungual blistering lesions), and dermal cocooning. Musculotendinous involvement may result in shortening of the exor tendons and intrinsic muscle contractures. Articular involvement produces stiff, subluxed, or even destroyed joints in older patients. Generalized osteoporosis and thinned, wedge- shaped distal phalanges may also be found. With each episode of relatively minor trauma to the hand, ulceration produces brinous adhesions and scarring, which results in the obliteration of web spaces, progressing to the ngertips and causing pseudosyndactyly. The same process occurs in the rst web space, initially causing an adduction contracture. This condition may also progress until the thumb is no longer independent. A grading system may be used to describe adduction deformity of the rst web space and pseudosyndactyly.

The severity of the disease is mainly determined by the particular form of the disease from which the patient suffers, but it is useful to broadly categorize the disease into the “nonscarring” and “scarring” (dystrophic) types. Pearson in 1971 rst classied the different aspects of EB.Furthermore, in 1989 the rst United Meeting on diagnosis and classication of congenital EB took place. In 2002, the second United International Meeting on the classication and diagnosis of EB changed the classication system. In particular, it has been attempted to simplify as much as possible the classication of EB, to reduce the numerous subclassication present in literature, even if with poor results (in the ofcial classication there are ten types of EB). At rst, they eliminate clinical aspects with a rare incidence or that cannot be considered as a separate clinical identity. Thus, more than 14 classes have been erased. Most eponyms have been erased in order to have the lowest number of categories. Nevertheless, some of them, as for example Weber–Cockaine disease or Hallopeau– Siemens syndromes, can not be abolished, because the names are of simple and direct approach and claim immediate images of clinical conditions well-known by the general physician all over the world. The removal of this eponyms could add further misunderstanding and moreover could even reduce the number of conrmed diagnosis.

The new categorization suggests to classify the patients affected by EB in three main groups, based on microbiological observation of the skin lesion and especially on the ultrastructural level of the cleavage in cutaneous area, utilizing nally the same criterion used by Pearson. The rst group includes EB simplex (EBS), in which the cleavage area and consequently the site of formation of blisters is inside the epidermal layer. Generally, the hands are affected, but heal without signicant scary tissue. The second group includes Junctional EB (JEB), in which the cleavage and the blisters formation happens exactly on the surface of the basal lamina, at the dermal–epidermal junction; also, this form doesn’t cause considerable scar. Finally, Dystrophic or

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Dermolytic EB (DEB) is characterized by blisters formation below the basal lamina. Due to the depth of these lesions, wounds healing causes the formation of retractile scars.

Inside the three main groups, there are further kinds of group with typical different characteristics.

In April 2019, some leading experts met in London, UK, to review the relevant data and to revise the system of classication of these disorders, considering in particular epidermolysis bullosa (EB), and focusing on the molecular etiology whenever possible. EB is the prototypic group of disorders with SF, dened by blistering from minimal mechanical trauma with disruption at the dermo-epidermal junction. The four major classical EB types are EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler EB (KEB). Other disorders with skin fragility, where blisters are only a minor part of the clinical picture or are not seen because skin cleavage is very supercial, are classied as separate categories. These include peeling skin disorders, erosive disorders, hyperkeratotic disorders, and connective tissue disorders with skin fragility. Because of the possible similar skin manifestations, these “EB-related” disorders should be considered in the differential diagnosis.

The proposed system is strictly clinically oriented. The classication of patients with skin fragility begins at the bedside and is based on personal and family history, as well as the presence or absence of specic clinical features. Only later on in the diagnostic process patients will be further classied based on specic molecular ndings.

The transmission of this pathology is inherited through an autosomic dominant mode for the EBS and autosomic recessive mode for the JEB. The DEB is autosomic dominant in some subtypes and autosomic recessive in the Hallopeau–Siemens. In particular, mutations in the same gene may be inherited in an autosomal dominant or recessive manner and may result in distinct clinical phenotypes (e.g., KRT5, KRT14, PLEC, COL17A1, or COL7A1). On the other hand, in DEB and EBS, similar phenotypes may

be either dominant or recessive or may be caused by mutations in different genes (e.g., COL7A1, KRT5, KRT14, PLEC, DST, EXPH5, or KLHL24). Prenatal testing and diagnosis have been available for more than two decades. Owing to the recessive nature of RDEB, unfortunately, parent’s carrier status is generally unknown, and such testing is rarely suggested. For all these reasons, the EB molecular classication is still complex.

Eisen (1966) and Bauer (1980) suggested that the pathology should be referred to a lesion of the gene which coded for a collagenases. More recent studies of 1991 and others demonstrated denitively that RDEB is linked to multiple different mutations in chromosome 3p21 of the COL7A1 gene that codes for type VII collagen. Type VII collagen composes the building block of anchoring brils proteins of the epidermal basement membrane. An abnormal type of this anchorin protein results in presence of blistering below the basal lamina, due to a defect of cellular adherence. Molecular biology represents the only possible eld to achieve the remedy of the pathology, because it is only by a substitution of the affected gene by a healed one that we can cure the disease. Even though a classication based only on molecular aspects has been proposed, actually molecular data don’t seem to be enough to create a correct and detailed classication. The acknowledgment possessed till now still not match perfectly with the different phenotypes of the disease, so that it is still so difcult to create a valid molecular classication.

19.2 Systemic Compromission

RDEB is the clinical condition requiring the most signicant care and medical assistance: in fact, almost each part of the body could be affected and progressively damaged by the pathology.

Hands involvement is almost certain. As previously said, little patient hands appear closed with st, with exed adducted thumb, often with partial or complete obliteration of the rst web. The interdigital webs also progressively diminish, with a process that is called pseudosyndac-

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tylization of the long ngers. Commonly nails are lost and sometimes the distal phalanx appears reabsorbed. Although the deformity results only from soft tissue contracture, secondary capsular and joint retraction, associated to tendon shortening, is a common nding.

Blistering lesions, frequently ulcerated, could be found in every district characterized by an epithelial layer, especially in skin regions more exposed to rubbing, as well as loss of cutaneous annexes and sometimes scarring alopecia.

Unfortunately, it is common to nd blistering lesions also in all the gastrointestinal tract. Oral and perioral blisters lead to microstomia; the esophageous mucosa is commonly affected by lesions and frequently presents scaring circumferential stenosis; perianal blisters and ssuring lead equally to stenosis and consequently to fecal retention. Such ndings lead to a malnutrition clinical picture resulting in the delay of growth, caused by the pain in feeding and defecation. Moreover, at the level of the intestinal tract, there is a reduction in the minimal rate of protein absorption across the affected mucous tissue.

In severe cases, also eye mucosa can be involved, with painful cheratitis, or sometimes symblepharon.

Generally, a varying degree of anemia is noticed, possibly due to the association of malnutrition and frequent and continuous bleeding.

The high rate of development of skin cancerous lesions in these patients can not be forgotten. It is well-known that patients affected with RDEB are exposed to a major risk of generating squamocellular carcinoma especially in the third and fourth decades. Other forms of EB (SEB, JEB) show an incidence of this pathology that can be related to the normal population. On the other side, patients affected with RDEB show 6% of probability to develop cancerous lesions at age of 20, 21% at 25 years, and 53% at 35 years. Therefore, it is mandatory, particularly after the rst two decades of life, an accurate monitoring of every change of the aspect, size, or color of all the skin lesions, for example, any ulcer which delay in healing or an abnormal thickness of the skin. It is in fact well-known that these patients do not have a really prolonged expectance of sur-

vival and the most frequent causes of death are infections, anemia, multi-organ failures following malnutrition, but also skin carcinomas.

19.3 Treatment

As previously said, hands are one of the most common affected sites within this pathology. The frequent use of the hand, in fact, exposes this district to recurrent and repeated trauma; moreover, even minor modications in hand anatomy (e.g., narrowing of the rst web) can result in a signicant functional impairment that could be initially compensated by the baby, but tend to progress in disabilities affecting a child’s most common daily activities.

It goes therefore without saying, that we should pursue a treatment as soon as the baby loses independence in hand movements and manipulation, due to the formation of the before mentioned “cocoon deformity”.

Conservative treatments are preferred to invasive approaches in case of mild to moderate deformities. Stretching exercises, protective and web retaining gloves, as well as splinting can help delay the comparison of rst symptoms and disease progression. Unfortunately, patients often refer to a specialist when the disease has become severely debilitating and hand functions are already compromised. At this stage, the management is unequivocally a surgical treatment.

Generally, surgery occurs when the patient is very young; the mean age of the rst surgery in fact is around 1–3 years. Young patients are usually operated under general anesthesia. In patients older than 14, a regional block can be proposed, especially for dressing. Anesthetic procedure is a delicate step and for this reason, well-trained anesthetic specialist and nursing teams are required for these patients.

At rst, any adhesive dressing can be used, because it is a further cause of lesion. Moreover, these babies present a small and fragile subcutaneous vascular system that lies beyond a very thick skin, due to scary tissue. For these reasons, the intravenous canulation procedure is very difcult. Also, endotracheal intubation requires a

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particular attention because of the already-mentioned microstomya and the delicate oral mucosa.

There is not an univocal opinion about the use of tourniquet. Some authors consider it useless and only a source of further trauma. According to other author’s experience, a careful installation of the tourniquet, avoiding any pressure point directly on the skin and reducing the pressure value, contributes to minimize blood loss and to reduce operative time.

Surgery begins with the degloving of the hand; afterward the opening of the rst interdigital web until the muscular level, associated sometimes at the release of the adductor pollicis brevis. Later the release of the palmar crease, with the stretching of the metacarpo-phalangeal joint, of the proximal interphalangeal joint and, if possible, of the distal interphalangeal joint, always avoiding tendons exposure and areolar tissue. K wires are inserted longitudinally to keep the ngers extended for the rst 2 weeks and then they are

removed in the rst change of dressing in sedation (Fig. 19.1).

Further medications are done until the hand is quite rehepitelized and the patient can tolerate the change of dressing without any sedation (Fig.19.2).

Since the morbidity caused by tissue withdrawal at the donor site often outmatches the advantages at the receiving site obtained after surgery, waiting for a spontaneous healing is often the best course of action. Many covering solutions have been proposed in different scientic works, most of them having already been tested in burn surgery. In our center, we used many of the proposed solutions, all presenting potentialities, as well as limits. Keratinocyte laminae could be for instance a valuable instrument, at least theoretically. Compared to skin graft surgery, which has the problem of the availability of sufcient tissue from our patients, the use of keratinocyte laminae poses no limitations in

Fig. 19.1 Case 1. Preoperative image showing “cocoon hand deformity” of both hands in a patient with EB and results obtained after its subsequent surgical treatment and dressing

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Fig. 19.2 Case 1. Postoperative images 2 weeks after surgery. Dressing is changed and re-epithelialization process has begun

C. Novelli et al.

terms of quantity. Moreover, skin grafts from our patients are often poor in terms of quality and present the same fragility as the receiving site. On the other hand, the extreme vulnerability of keratinocyte laminae denitely represents a limitation to its use.

The operation ends with the application of dynamic splint, which consists in a thermoplastic material. The splint is used to exercise an extension traction on the long ngers and thumb; elastic bands are connected by one side to the splint and on the other side anchored to each digital segment, through a transversal Kirschner wire which has previously been passed through the last phalanx. This last procedure in our experience seems to be the key in improving the surgi-

cal results, and mostly increasing the relapse-free interval. The splint in fact allows progressive distension of the ngers without employing an excessive forced extension during surgery. The latter could cause tendons exposure, which could not be covered due to the poverty of available grafts. Moreover, the application of the dynamic splint allows a good performance of dressing during the postoperative period, reducing the action on the nger and so preserving the granulating tissue, and reducing pain.

Dressing is delayed as far as possible in order to favor a leaded spontaneous wound healing. Only in case of infection dressing could be anticipated, although, on the contrary on what could be thought, these episodes are extremely rare.

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Fig. 19.3 Static splint is used after surgery to provide a passive stretch maintaining the optimal position of ngers. Later on splint is recommended also overnight

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Routinely bandage is removed at the 15th, 30th, and 45th days postoperative. During the last period, it is possible to let the hand free from bandage and to begin active rehabilitation even before removing the dynamic splint.

Rehabilitation must begin early: intraoperative positioning of the splint can be considered the rst physiotherapeutic step. The aim of rehabilitation program is to ght the retraction tendency of the scars, that is enhanced by the pathophysiology of the disease, but also taking care of the fragility of the newborn cutaneous tissue, because of the risk to cause new skin lesions. The opened hand position gained with surgery is rst maintained by a valve splint. When all the wounds are healed and the status of the skin allows it, the splint is substituted with a dorsal static splint eventually converted in dynamic with a progressive traction on each nger, to maintain the extension strength. This splint can be modied according to the different adaptations of the new anatomical feature of the hand (Fig.19.3).

As previously said, EB is characterized by frequent relapses. Surgical results should be considered “unsatisfactory” when relapse occurs within 2 years from the rst surgery, “good” if it occurs within 2–4 years and “excellent” after 4 or more years. At relapse, a second operation results necessary. However, the concept itself of “relapse” is difcult to understand in this particular pathology. A deviation in exion of the fourth and fth nger is quite common, but this condition is absolutely compatible with a reasonable functioning hand; on the contrary, even a slight restriction of the rst interdigital space can hinder the use of the hand itself, due to the impossibility of grasping large objects. Surgeon should pay attention to follow the evolution of the pathology, intervening only according to the demands of the patients and not aiming to maintain categorically the hand opened. This last behavior risks to lead to an increased and unjustied number of surgical procedures in the patient history (Fig.19.4).

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Fig. 19.4 Case 1. Postoperative images showing maximal opposition and full range of movement both in power and precision grips obtained after surgery

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19.4 Natural History

The clinical features and complications of different forms of EB often change and evolve over time and this is important in order to recognize the different subtypes and anticipate the clinical course and related problems. Natural history of the disease partly reects different stages in

child’s growth. However, certain subtypes of EB have a natural evolution with varying degrees of severity in which specic clinical signs can be observed or disappeared over time.

Distinguishing the major subtypes of EB in the neonatal period considering only clinical features is extremely unreliable and this highlights the need for rapid and accurate laboratory diag-

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nosis. Blistering lesions in babies often have a predilection for the extremities and around the diaper area, but, as the child grows up, the pattern of blistering will usually become more characteristic of its subtype. For example, in localized EBS blisters will form predominantly on feet, whereas in intermediate or severe DEB subtypes, fragility will become more marked over bony prominences, such as the knees and elbows. While babies with severe JEB may have relatively little skin blisters at birth, over the rst few months the characteristic granulation tissue affecting the face, ears, and distal digits becomes more prominent and distinctive. In KEB, early childhood blistering lesions resolve as photosensitivity and progressive poikiloderma become more evident.

Some sequelae of EB are irreversible and progressive, for example, skin and oral mucosal scarring or nail loss in DEB; therefore, they tend to become more marked with age. In severe EBS, infants have very severe and extensive skin blisters and this subtype can have a lethal course. However, the course of disease improves over time, such that adults may have very limited blisters conned largely to acral sites. The clinical features of EBS with mottled pigmentation also change over time, often with blistering improving throughout childhood, paralleled by the development of the characteristic pigmentary changes unrelated to previous sites of blistering and punctate palmoplantar keratoses. Intermediate EBS with KLHL24 mutations is notable for its severe skin loss at birth which gets better with age, and also by the development of cardiomyopathy in early adulthood. Similarly, in EBS with PLEC mutations, SF is accompanied by the onset of progressive muscular dystrophy at any point between infancy and adulthood and has also been associated with cardiomyopathy.

The extent and pattern of blistering may vary in distinct forms of EB. For example, RDEB inversa usually comprises intermediate severity of generalized blisters early in life, but later, in childhood to adulthood, the sites of predilection become markedly exural. Pruriginosa DEB also evolves over time, with the development of prurigo-like nodules and linear lesions on the lower

legs initially, spreading generally more proximally and also onto the arms. The onset of specic pruriginosa features may be extremely delayed, with onset in late adulthood.

Similarly, the distribution of localized pretibial DEB evolves with age. In late-onset JEB, SF tends to start in mid-childhood with progressive scleroderma-like atrophy and nail changes developing subsequently. A number of cases of severe JEB in infancy have been associated with spontaneous improvement and longer-term survival; in such cases, LAMB3 mutations, resulting in a truncated but partially functional b3 laminin chain, have been postulated to result in an intermediate clinical picture.

The mechanisms behind the distinct patterns of distribution and their uctuation over time in different subtypes of EB are not fully understood, but likely reect specic genetic consequences at a protein level. Further elucidation of genotype– phenotype correlation in EB-causing genes as well as other genetic modiers, may provide some clarication in time.

In addition to disease-specic natural history, EB may be accompanied by many secondary complications that develop over time and often depend on the general severity of the EB type, as well as environmental and confounding factors, such as bacterial colonization. For example, anemia, reduced bone mineral density, renal impairment, progressive skin contractures, and the development of squamous cell carcinoma are all potential complications of severe RDEB and their onset depends on interindividual variability.

Revisions of the EB classication is closely linked to scientic developments in diagnostic and research and should be a useful tool for researchers and clinicians dealing with patients with EB (for counseling, prognostication, followup, and screening for complications). Emerging therapeutic options and clinical trials open new perspectives and underscore the importance of molecular genetics and genotype–phenotype correlations to predict therapeutic options for precision medicine.

EB-associated proteins have distinct roles in assuring the mechanical stability of the cells and

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adhesion, as well as structural and functional particularities (e.g., laminin 332, integrin a6b4 87, or collagen XVII 88in controlling keratinocyte stemness). Yet, there are common pathogenetic mechanisms, such as chronic tissue damage and inammation, that apply to all/several types of EB.

Some therapeutic principles, like induction of read through of PTC mutations, RNA-based therapies (e.g., antisense oligonucleotides for exon skipping 93), or modulation of protein misfolding, may be applied for different genes/proteins, under the premise of knowledge of individual mutations and their consequences. Therefore, subclassication of EB and SF disorders based on the molecular defect, and stratication of mutations for precision medicine is a tempting challenge for the future.

19.5 Conclusions

Several surgical approaches have been proposed in the literature for congenital EB and they all differ for the extension of the surgical technique. Various scientic works have proposed large skin graft obtained from lower limbs, with successive frequent dressings and heavy immobilization (also in plaster). The results of such techniques seem not to be better both in early postoperative period and in long-term controls when compared to less invasive scheme.

Since EB is a pathology that limits dramatically the quality of life of the patient and reduces his lifespan, a more physiologic approach should be preferred.

The nal goal is to grant patients some level of independence in their personal life, making them capable of satisfying their primary needs by at least carrying out gross movements with their hands.