INTRODUCTION

The term epidermolysis bullosa (EB), introduced in 1886, refers to a group of hereditary blistering diseases characterized by blistering on the skin and mucosa caused by minimum mechanical trauma ^1,2. EB is associated with protein changes that cause defective adherence between skin structures, leading to blistering ³. Traditionally, four main types of EB have been identified based on distinct differences at the ultrastructural level where the blisters develop: EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and a mixed type EB called Kindler syndrome (KS) ^1,2.

EB severity varies from mild to severe, and skin involvement may be localized or generalized. Skin findings may include blisters, scars, changes in pigmentation, alopecia, absent or dystrophic nails, and hand or foot deformities ^4,5. Some types of EB may also cause extracutaneous manifestations. Nutritional status may be compromised by clinical oral, pharyngeal, esophageal, and gastrointestinal manifestations that limit food intake and absorption. Hypermetabolism resulting from skin lesion inflammation may also occur (6). Nutritional involvement in EB is directly related to the severity of the associated clinical complications ⁶.

Since complications vary in number and intensity over time, it is very difficult to assess whether EB individuals have adequate growth and nutritional status. Weight and growth rate monitoring is a recognized way to verify the growth adequacy of healthy children, but comparison of healthy children's growth rates with those of children with EB has limited value ⁷. Despite knowledge of the nutritional risk of EB individuals, no assessment parameters exist, and growth charts for healthy children continue to be used ⁸.

This study investigated the following nutritional status indicators in children with EB: exclusive breastfeeding duration, problems caused by introduction of complementary foods, birth weight and length, and growth curves of children with EB.

MATERIALS AND METHODS

The present descriptive, retrospective clinical cohort study was approved by the Research Ethics Committee of the School of Health Sciences of the University of Brasilia under protocol number 120/12. All subjects provided informed consent. The study included all confirmed cases of EB aged less than 19 years, treated at the Pediatric Nutrition outpatient clinic of the University Hospital of Brasilia, a reference public service opened in 1998. The clinic employs a multidisciplinary team who has assisted roughly 20 patients and currently follows ten patients. Some patient data were collected from the medical records, such as the information registered between August 1998 and May 2013, which included sociodemographic characteristics, age at diagnosis, birth conditions, and anthropometric measurements collected during the entire follow-up period. Given the skin fragility of these patients, anthropometric assessment consisted only of weight and height measurement. Skinfold thicknesses and perimeters were not measured because the instruments needed for these measurements would press or pinch the skin.

Weight and height as a function of age and gender were presented in growth curves by percentile (p). The WHO growth curves height-for-age (H/A), weight-for-age (W/A), and body mass index (BMI)-for-age (BMI/A) were used ⁹. Since the W/A growth curve only assesses W/A until age ten years, the children's curves were limited to this age or to the nearest age with recorded weight.

The WHO programs Anthro and Anthro Plus ¹⁰ produced graphs of individual anthropometric measurements over time. The following variables were assessed during the interview, when the informed consent form was signed: exclusive breastfeeding duration, problems caused by the introduction of complementary foods, age at diagnosis, and birth length and weight. Chronological age on the last assessment was compared with the age that corresponded to height at p25 (A/H25th). This comparison was done because the equation that estimates the energy requirement of EB patients ⁶ uses p25 as reference of adequacy. The data were presented as years of difference between the chronological age and A/H25th.

RESULTS

Ten cases of EB were studied, seven of the recessive dystrophic EB (RDEB) type and three of the EB simplex (EBS) type. The mean age was ten years, ranging from one to 18 years. Age at diagnosis varied from the first day of life until after the first year of life. All patients were born at term, and nine cases had birth weight of 2,500 grams or more. The child with low birth weight had RDEB.

Nine children were breastfed. One child with RDEB was not breastfed because of the clinical manifestations of the disease. Three of the breastfed children were exclusively breastfed for six months. One child was exclusively breastfed for 18 months, also because of the clinical manifestations of the disease, which prevented the child from accepting complementary foods. Problems related to the clinical manifestations of the disease caused by the introduction of complementary foods (Table I) did not occur in children with EBS, but they occurred in four children with RDEB. No patterns were found regarding the type of problem the children experienced.

Table I Characterization of the cases, exclusive breastfeeding duration, and problems occurred during the introduction of complementary foods 

y: years; m: months.

Nine patients had birth H/A higher than height at p3. This comparison could not be done for one patient because his birth length had not been recorded in the medical record.

The percent adequacy of the chronological age with respect to A/H25th was ≥ 100% for all children with EBS, but children with RDEB had percent adequacy < 90%, confirming growth impairment. The difference between chronological age and A/H25th varied from four months in the youngest patients to five years and ten months for the oldest patient. When sex was considered, the biggest difference was found in a female patient. The last anthropometric assessment included in this study found that all RDEB patients were underweight and stunted. One EBS patient presented excess weight (Table II).

Table II Anthropometric data at birth, difference between the chronological age and age corresponding to height at the 25th percentile, and current nutritional diagnosis, according to growth curves 

EB: epidermolysis bullosa; RDEB: recessive dystrophic epidermolysis bullosa; EBS: epidermolysis bullosa simplex; cm: centimeters; g: grams; p: percentile; H/A: height-for-age; ND: no data; y: years; m: months; A/H25th: age corresponding to height at the 25th percentile. *Very low weight-for-age. †Low weight and height-for-age. ‡Very low weight and height-for-age. §Very low height-for-age. |Obese child, appropriate height-for-age. ¶Low weight and appropriate height-for-age. **Appropriate height-for-age. ††Appropriate weight and height-for-age, eutrophic child.

The growth curves based on data from the first to the last assessment show that all EBS patients had ascending W/A curves, and their results were equal to or above those at p3 (Fig. 1).

Figure 1 

One patient had W/A equal to or above p85, and after age six years, it increased to p97. Six of the seven patients with RDEB had W/A growth curves below that for p3 in the first visit, during the entire follow-up period, and in the last assessment conducted by this study. One patient had W/A growth curve equal to or above that for p3 between the second and third year of life, but after the third year of life until the last assessment, his curve remained in the same pattern as those of other children with RDEB, that is, below the curve for p3. The H/A and BMI/A growth curves could not be constructed for one patient because of severe lower limb contractures, difficulty to maintain the back and neck straight, and fused feet and ankles.

Three of the seven patients with RDEB had H/A growth curves below that for p3 from the first assessment, which occurred between ages 24 and 48 months. EBS patients did not have impaired growth.

The BMI/A curve of the RDEB children confirmed the underweight of four patients, but the curves of two patients were equal to or above that for p3.

Regarding the difference in years between the chronological age and the age corrected according to current height for the p25 growth curve, RDEB patients differed from EBS patients. Although age at EB diagnosis varied, all RDEB children had W/A curves below that for p3, from the first to the last assessment, or during most of the outpatient follow-up period.

DISCUSSION

To the best of our knowledge, this is the first study to investigate nutritional involvement, exclusive breastfeeding duration, and problems caused by the introduction of complementary foods in EB children conducted in University Hospital of Brasília. We hope this information will contribute to the establishment of the nutritional profile of EB individuals, especially in the first year of life.

EB children may be born with normal weight, but in some cases low weight may begin in the uterus. Fox, Alderdice, and Atherton ¹¹ found that English RDEB children had significantly lower birth weights than their healthy counterparts. On the other hand, the present and other studies ^12,13 found that term children generally born with normal weight- and length-for-age stopped growing and gaining weight properly after the clinical manifestations of the disease appeared, as they compromised food intake and increased nutritional requirements. These divergent results indicate the need of more studies that thoroughly investigate birth conditions and short-, medium-, and long-term nutritional involvement.

This study was not able to assess whether nutritional deficits were associated with late disease diagnosis. Nevertheless, in the same way that prognosis is related to EB type ¹⁴, it is plausible that worse nutritional status is present in the severe EB types. Other studies may be able to clarify whether early EB diagnosis, especially in the more severe cases, results in better growth.

The WHO recommends exclusive breastfeeding for six months and complemented breastfeeding for two years or more. This practice efficiently promotes proper growth, avoids infant death, diarrhea, and respiratory infections, and reduces the risk of allergies and obesity, among many other benefits ^15,16. Literature data on the breastfeeding duration of EB children were not found, but the onset of manifestations may significantly affect the exclusive breastfeeding duration.

According to the WHO, the foods introduced after age six months should complement the numerous qualities and functions of breastmilk. In addition to meeting nutritional requirements, the introduction of complementary foods helps the child to progressively acquire the caregiver's food habits. Moreover, entering a new life stage, where children are exposed to new tastes, colors, aromas, textures, and knowledge, requires an adaptive effort ¹⁵. Similar to the present study, Birge ¹² found that EB manifestations compromise food intake. Haynes ¹⁷ states that the critical interference on food intake begins during dentition and diseases that occur in the first year of life.

The study findings regarding the weight and height of EB children are similar to those in the literature. Birge ¹² used growth curves from the National Center for Health Statistics to assess 60 patients with EBS, JEB, and RDEB aged two weeks to 18 years and found that 77% of the 35 RDEB patients had weight-for-age below p5, and 60% had height-for-age below p5. Barbosa et al. ¹⁸ assessed gastrointestinal signs and symptoms and nutritional aspects of children with different types of EB and found that the weight and height of 63.1% of their sample were below p2.5. Colomb et al. ¹⁹ found that RDEB children start to show delayed growth at a mean age of 4.9 years. The present study could not find length data before age 24 months, so it was not possible to determine when delayed growth began, but it may have been between the first year of life and the age at the first visit since all patients had normal birth length.

Regarding BMI, other studies have also found low BMI in a high percentage of individuals with the more severe types of EB. Barbosa ¹⁸ determined nutritional risk by assessing the growth parameters of children with EBS, JEB, and RDEB, and found that 22%, 57%, and 77%, respectively, were at risk of malnutrition. Stunting, which is normally attributed to chronic energy-protein malnutrition, was found in 11% of EBS children, 29% of JEB children, and 60% of RDEB children ¹⁸. The high percentage of malnourished RDEB children is also evidenced by the nutritional status diagnosis of the study sample. Generally, although RDEB is a severe disease subtype, the study RDEB patients did not have the same growth pattern, and some were more malnourished than others. Yet, they were all malnourished and grew less than EBS patients, whose growths were within the WHO curve. Martínez ²⁰ suggests that most RDEB patients have delayed growth, which worsens over time, a finding confirmed by the present study: as age increases, the differences between the patient's weight and height and the reference weight and height increase.

EB children and adolescents have higher energy and nutrient requirements because of the constant blister healing process, skin losses, skin heat loss, and inflammatory and infectious processes that may affect the lesions ⁷. The association between low food intake and higher nutrient requirements compromises nutritional status and consequently, leads to malnutrition ²¹.

Therefore, weight and height should be measured in short intervals to allow an appropriate and timely intervention.

The study limitations include its retrospective character, the lack of complete weight and height information in the patients' medical records, and the possible measurement errors. Although measuring weight and height is a simple procedure, doing so in children with pain, infected blisters, difficulty to extend the lower or upper limbs, and restricted ability to maintain the back and neck straight constrains the use of standard measuring procedures.

The great advantage of the present study is that it brought to light information about the nutritional aspects of EB children as it is in this age group that it is possible to minimize nutritional sequelae, promote growth, development, and better quality of life, and optimize the appropriate interventions. Supposedly, breastfeeding and no complementary feeding problems were not enough to prevent inadequate nutritional status, observed in the majority of the study children. The original presentation of the growth curves of children with EB may help to determine nutritional involvement and to establish how these children grow. Nonetheless, more studies, especially prospective cohort studies about growth and feeding in the first year of life, with well-defined methodologies, are needed to better understand and contextualize these data for later use by services that treat this population. Future studies should also assess the need of creating specific growth curves for children with the more severe types of EB.