Anemia is a common and often serious complication of generalized forms of EB such as RDEB and JEB. Data from the National Epidermolysis Bullosa Registry showed the prevalence of anemia at time of presentation to the registry to be 37.8 % in those with JEB and 49.1 % in those with RDEB [1]. The severity of anemia varies, and hemoglobin levels as low as 5–6 g/dL are unfortunately not uncommon. Anemia produces symptoms that have a negative impact on quality of life such as fatigue, lack of energy, poor endurance, and loss of appetite. Low hemoglobin levels also contribute to poor wound healing.

The pathophysiology of anemia in EB is likely multifactorial—a combination of iron deficiency and anemia of inflammation (i.e., chronic disease), although a systematic study fully examining the problem is lacking. Patients with EB may have accelerated loss of iron via the skin due to sloughing of the epidermis and oozing from open wounds. In addition, involvement of the gastrointestinal tract may contribute to iron loss, and oral and esophageal disease may limit the intake of iron-rich foods such as meat. Absorption of iron may also be compromised by abnormal integrity of the gut mucosa. Finally, many patients with generalized EB show chronically elevated markers of inflammation, likely the result of chronic wound healing. Inflammation leads to inefficient utilization of iron in hematopoiesis and ineffectiveness of erythropoiesis [2]. Laboratory studies in patients with generalized EB typically show microcytic anemia with reduced hemoglobin, hematocrit, and total iron levels. Ferritin levels are not a good indicator of iron deficiency EB as they may be elevated due to inflammation. Patients with JEB and RDEB should have their complete blood count and iron studies performed initially and at 6 month intervals initially for RDEB and more often in H-JEB. Any patient with EB with signs or symptoms to support anemia (fatigue, pallor, tachycardia) or known problems with anemia should have a more detailed profile more often. Vitamin B12, folate, and other mineral deficiencies should also be evaluated if indicated. Soluble transferrin receptor (STR) can be helpful in the setting of chronic anemia with raised ferritin due to inflammation, to determine if the patient is truly iron deficient or not. A raised STR indicates true low body iron stores and a low STR, raised body iron levels. Remember to consider thalassaemia trait as a cause of deranged values, as overloading these patients with iron infusions can lead to organ damage, such as to the liver and heart.

Treating the anemia seen with EB can be challenging. Ideally, starting iron-rich foods and a daily multivitamin with iron at a young age could help to prevent anemia or minimize its severity; however, this strategy is not perfect. Screening laboratories can help identify anemia before the symptoms become overt. Oral iron is indicated for patients with mild anemia (hemoglobin of 10–12 g/dl), but unpalatable taste of some forms, irritation, and constipation may limit compliance. In addition, it is possible that absorption from the gut may be inadequate. Concurrent supplementation with vitamin C may help improve the absorption of oral iron.

Patients with more moderate anemia (Hg 7–10 g/dl) are unlikely to improve with oral iron and intravenous iron is indicated to restore iron reserves. Initial evidence came from a small case series showing a benefit of iron dextran and erythropoietin on hemoglobin in patients with RDEB and JEB [3]. In addition, two case reports in 1999 suggested the benefit. Atherton and colleagues [4] reported a 7-year-old boy with RDEB who had anemia refractory to oral iron and oral iron plus erythropoietin in whom infusions of iron sucrose led to increases in hemoglobin and mean red cell volume. Antunes and colleagues [5] described a 20-year-old woman with RDEB, renal disease, and transfusion-dependent anemia who stopped receiving transfusions after starting weekly iron infusions and erythropoietin. Finally, Kuo and colleagues [6] reported four patients with RDEB who sustained higher levels of hemoglobin after starting parenteral iron and darbepoetin. Compared with iron dextran, iron sucrose and ferric gluconate complex are less immunogenic and less likely to cause anaphylaxis and are thus preferred for patients with JEB or RDEB in whom oral iron therapy is not tolerated or is ineffective. Many unanswered questions persist about the optimal use of iron infusions in EB. Frequency of dosing depends on the severity of anemia and availability of intravenous access. In addition, whether or not concurrent erythropoietin provides additional benefit is unclear. Using erythropoietin without iron supplementation in patients with EB is not indicated.

Finally, red blood cell transfusions are indicated for EB patients with severe anemia (<7 g/dl) or patients who require a rapid restoration of hemoglobin in order to tolerate surgery or procedures.

Wounds in EB are colonized with bacteria which reside in the skin and which come from the gut flora during bathing and toileting activities. These bacteria include Staphylococcus epidermidis, Staphylococcus aureus, Bacteroides species, Pseudomonas aeruginosa, E. coli, and sometimes Proteus and Klebsiella species. Chronic colonization of wounds can lead to ongoing inflammation and delay in wound healing. Unlike most other conditions in which there are chronic wounds, in EB there is a good blood supply, promoting inflammation. There is no excess of blood glucose in EB wounds like in diabetes, but because of blood loss, anemia, and micronutrient deficiencies, such as iron, zinc, and vitamin C, EB wounds in more severe forms of EB do not heal as quickly as those in patients with milder forms of EB. Hence, although there is no epidemiological data on this, it is the more severe RDEB and JEB patients who have the majority of these chronic wounds, lasting at least 8 weeks in one location along with larger areas of wounds.

It is only when the wounds are critically colonized that there can be risk of infection, with clinical signs such as a fever, redness, heat, significant malodor, increased exudate, and pain appearing which is different in the infected wound compared to colonized wounds. In this case, a skin biopsy for culture is the gold standard for confirming the infection, but painful and traumatic for the patient, so usually wound swabs are done to identify the bacteria and what its sensitive. Clinical judgment continues to prevail when deciding whether to treat with topical or systemic agents or when no treatment is needed. Treatment should be initiated only in these circumstances, because otherwise, chronic use of antibiotics would results in resistant strains of these bacteria appearing.

There is no international consensus on what is best to prevent critical colonization and infection in EB wounds. Many centers are using bleach baths once to twice per week to try to reduce colonization. Patients tend to prefer the bathing to showering due to the pain that direct sprays of water can generate in their wounds. In some countries, bathing is not routinely used and only certain areas or wounds are changed and cleansed individually. However, in hotter countries such as the Asian and Australian region, patients will not tolerate that due to sweating and malodor of their normal skin and other wounds. Bathing does have the potential disadvantage of having gut flora more likely to spread from the perianal area to the water and thence to other wounds. One way of minimizing that would be for the patient to have that area cleaned first with a shower/hose over a toilet/bidet, as it is prevalent in many Muslim countries to keep clean. Other institutions advocate the regular use of rotating topical antimicrobials, but infectious disease experts are not keen on this approach as even if they are rotated every couple of months, patients may be tempted to use them intermittently and this leads to resistant bacteria in the community. The cheapest antimicrobial available is silver sulfadiazine, often recommended for burn patients, but easy access to this preparation by EB patients from their family physicians has led to not only resistance but a number of argyric patients with permanently purple faces. There is also concern that buildup of silver in the body may damage the brain and kidneys. Hence, the UK EB dressing scheme recently removed all silver dressings from its list of approved dressings. In the Australian EB dressing scheme, these silver dressings can only be given with the EB dermatologist’s prescription via the scheme and for a maximum of 2 months per 6 month cycle.

The choice of systemic agent to use should be dictated by the sensitivities and for the shortest period of time needed to reduce the likelihood of resistance which could lead to MRSA and, even worse, vancomycin-resistant enterococcus. Sepsis is one of the leading causes of death in EB, and so regular and prompt review of patients with wounds which are behaving differently to their usual wounds is important. Consulting with the infectious disease team is also important for the more severe cases.

Childhood and adolescence are normally times of rapid bone growth and bone mineral accrual. Peak bone mass is reached in early adulthood, and the failure to attain adequate bone mass during this time increases the risk for osteoporosis and pathologic fractures, both at present and later in life [7]. In addition to one’s genetic background, factors such as overall nutrition, calcium and vitamin D intake, weight-bearing activity, and hormonal status determine the likelihood of attaining adequate peak bone mass. Low bone mass has been described in many chronic childhood illnesses and conditions and is likely multifactorial in nature [8]. Osteopenia (low bone mass), osteoporosis, and pathologic fractures are associated with generalized forms of EB, particularly JEB and RDEB.

Radiographic evidence of osteopenia in DEB was first reported by Wong and Pemberton [9], and pathologic fractures have been reported in RDEB and JEB as well [10–13]. Potential contributors to poor bone health in EB include nutritional inadequacy, vitamin D deficiency, inactivity, hormonal abnormalities (e.g., delayed growth and puberty), and chronic inflammation. A cross-sectional, observational study of bone metabolism in seven Chilean patients with generalized forms of EB found low bone mineral density (BMD) in three patients, all of whom had low 25-OH vitamin D levels and severe limitations on activity [14]. Fewtrell and colleagues described the results of bone density studies in 39 EB patients, showing that compared with healthy peers and those with EBS, RDEB and JEB patients tended to have lower BMD, even after adjustment for small body size [15]. In this population, serologic evidence of bone pathology or vitamin D deficiency was not seen. In a prospective study of 20 subjects, Bruckner and colleagues confirmed that patients with severe, generalized RDEB have low BMD, which correlated with short stature, delayed skeletal maturity, reduced mobility, greater extent of skin blistering, evidence of undernutrition, anemia, and chronic inflammation [16]. A follow-up study of a subset of these subjects showed that while many gained bone mineral content and BMD over a 1-year period, the gains fell short of expected increases for age, thereby resulting in reduced bone mass [17].

The literature and experience in EB centers suggests that in order to reduce the risk for osteoporosis and pathologic fractures in patients with EB, efforts must begin in infancy and early childhood to support healthy bone growth. Such efforts include optimizing nutrition, supplementing calcium and vitamin D, and encouraging gentle weight-bearing activity as tolerated. Vibratory platforms, a nontraumatic means of providing mechanical loading to bones, have been found to be helpful in children with developmental disabilities [18] and may have a role in patients with EB. Routine screening laboratories should include serum calcium and phosphate, 25-OH vitamin D levels, and alkaline phosphatase. The optimal frequency of dual-energy x-ray absorptiometry (DXA) studies for patients with EB has not been determined, but for patients with RDEB and JEB, an initial DXA of the lumbar spine can be obtained when the child is able to hold still for the duration of the study (typically around age 6) and be repeated every 1–2 years thereafter. Interpretation of DXA results should be done in conjunction with someone with experience in pediatric bone metabolism. Plain radiographs are useful to evaluate for occult or pathologic fractures and are indicated in the evaluation of pain. Bisphosphonates are indicated for the treatment of disabling pathologic fractures, and potentially bone pain, in patients with EB [11–13]. At this time, however, there are inadequate data to recommend their use to prevent fractures in children with EB and low BMD.

Gastrointestinal (GI) complications have been described in all EB types and are responsible for significant morbidity in these patients. The more frequent GI complications described in EB patients are dysphagia, esophageal stenosis, gastroesophageal reflux, constipation, diarrhea, abdominal pain, protein-losing enteropathy, and anal fissures [19]. All of these complications interfere in different ways with patient’s food intake, nutrient absorption, digestion, and quality of life and make the optimization of their nutritional status a real challenge.

Freeman et al. published a retrospective study on 223 EB patients that showed GI complications were present in 130/223 (58 %) of them [19]. In EB simplex, constipation and gastroesophageal reflux (GOR) were often observed. In JEB, failure to thrive and protein-losing enteropathy were the most frequent GI manifestations. Constipation was common in patients with dystrophic EB (DEB) and often they required laxatives and in some cases fiber supplementation. GOR affected three-quarters of those with recessive DEB, two-thirds also having significant esophageal strictures. Over half of patients with recessive DEB required gastrostomy insertion. Diarrhea affected a small but significant proportion of children with recessive DEB with macroscopic and/or microscopic changes of colitis in the majority [19].

Data from the National Epidermolysis Bullosa Registry suggested that esophageal complaints correlate with the relative severity of the underlying EB type (EBS<JEB<DEB). The cumulative risk of esophageal stenosis or strictures was striking, particularly in RDEB (6.73, 35.19, 57.40, 79.14, and 94.72 % at ages 1, 5, 10, 20, and 45, respectively), leading to an increased need for esophageal dilatations [20]. Constipation was also a common complaint, reported in 77 % of two RDEB subtypes, RDEB Hallopeau-Siemens subtype (RDEB-HS) and RDEB inversa (RDEB-I); in 50 % of RDEB non-Hallopeau-Siemens (RDEB-nHS); and in approximately 20 % of JEB and DDEB [15]. The need for gastrostomies is also very high, reported in 40 % of JEB-Herlitz and 4.2 % of RDEB-HS [20].

One of the most debilitating features of EB is the development of esophageal strictures, which produces profound dysphagia, exacerbating an already highly compromised nutritional status common to these patients. Esophageal strictures and growth retardation were commonly seen among the more severe EB subtypes, most notably Hallopeau-Siemens recessive dystrophic EB, and occur as early as the first year of life [20].

For patients with RDEB that present strictures, balloon dilatation of these is the therapy of choice and has been shown to be safe and effective [21, 22]. The use of corticosteroids after this procedure can prevent early restenosis and is usually given at a dose of [23] 1–2 mg/kg/day of prednisone at the time of dilatation, followed by tapering dose for the following 5 days [24].

Diet recommendations to reduce esophageal stenosis have also been described. Pureed or semiliquid food cause less trauma, while hard food particles may induce blistering and result in scarring of the upper esophagus. One should also consider that larger food particles may result in obstruction particularly if the patient has an esophageal stricture [21].

Another frequent gastrointestinal complication in EB patients is gastroesophageal reflux (GER). To prevent this complication, one of the main objectives is to reduce gastric acidity. The use of proton pump inhibitor or H-2 blocker in EB patients is frequent but there are only few publications about this topic [24]. Their use can decrease the symptoms of gastroesophageal reflux, but there is no strong evidence to support that their use can decrease or prevent the incidence of esophageal stenosis, dysphagia, or abdominal pain. Also it was described fundoplication as a treatment for gastroesophageal reflux disease in EB patients [25].

Other important gastrointestinal preventable complications in EB are chronic constipation, painful defecation, and fecal impaction that frequently contribute to malnutrition and growth failure. Standard treatments for constipation, such as increased intake of conventional dietary fiber and fluids and/or the use of laxatives and stool softeners, are largely unsuccessful. Hanes et al. evaluated with a questionnaire the use of a fiber-containing liquid formula (Enrich) in 20 chronically constipated children with dystrophic EB. All derived substantial improvement in constipation when taking 250–750 ml Enrich per day. These authors recommended that fiber-containing food should be prescribed for chronic constipation in EB. In cases of fecal impaction, this should be preceded by bowel cleansing [26]. Polyethylene glycol and lactulose are two medications used to prevent constipation in EB patients. Anal fissure are prevented decreasing constipation. The use of zinc oxide cream that is a topical treatment to decrease the local pain and improve wound healing in the affected area. Important medication such as oral iron and zinc can increase constipation. The substitution of iron IV for the oral preparations can prevent this complication.

Some of these complications can be lethal, such as pyloric atresia in some EBS with plectin mutations and alpha6beta4 integrin deficiency. Ultrasound during pregnancy can make the diagnosis and help program a surgery after delivery to correct the defect.

The first report of genitourinary involvement in a patient with EB was published by Kretkowski et al. in 1973, and after this publication many others have also reported regarding this association [27]. Different types of GU complications have been seen in the different types of EB. These include amyloidosis, hereditary nephritis, postinfectious glomerulonephritis, IgA nephropathy, urinary tract obstruction, and renal failure among others. The true incidence of these complications has not been established, but the National Epidermolysis Bullosa registry reported that urinary tract complications occurred in a minority of patients across all types of EB. According to their data, GU difficulties were reported in 16.6 % of patients with EBS, 30.2 % of JEB patients, 19.9 % of DDEB, and 31.1 % of RDEB [28]. Fine et al. reported data on urethral meatal stenosis, urinary retention, bladder hypertrophy, hydronephrosis secondary to ureteral strictures, pyelonephritis, and cystitis, but no data was reported in other known GU complications. Taking into account all types of nephro-urological involvement, it has been postulated that causes can be grouped into three major groups: obstructive uropathies, acute or chronic glomerulopathies, and amyloidosis [29]. Regardless of the cause, many of these can lead to chronic renal failure in EB patients.

Since the first report of squamous cell carcinoma (SCC) arising in EB was published in 1913 [51], a large number of peer-reviewed papers have been published detailing this severe and often fatal complication. SSC can arise in all major forms of EB; although by far more commonly observed in patients with severe generalized recessive dystrophic EB (RDEB), SCCs may occur in the context of milder recessive and dominant forms of dystrophic EB [52], non-Herlitz junctional EB (JEB) [53, 54], EB simplex (EBS) [55], and Kindler syndrome [56, 57]. These highly aggressive tumors present considerable clinical challenges, particularly in terms of distinguishing tumors from nonmalignant EB wounds, ongoing surveillance, and management of primary tumors and metastatic spread. Advances in our understanding of the basic science underlying these tumors may provide insight allowing the development of novel therapies [53, 58, 59]: in the meantime, however, there is a real need for clinical trials of existing strategies for monitoring and treating EB SCCs.