A single-centre study on predictors and determinants of pubertal delay and growth impairment in Epidermolysis Bullosa.

BACKGROUND: Delayed puberty is a possible complication of Epidermolysis Bullosa (EB), though the actual incidence is still unknown. In chronic illnesses delayed puberty should be correctly managed since, if untreated, can have detrimental effects on adult height attainment, peak bone mass achievement and psychological health. AIMS AND METHODS: This is a single-centre study on pubertal development, growth and bone status in EB. Auxological, densitometric (areal Bone Mineral Density-aBMD Z-score, Bone Mineral Apparent Density-BMAD Z-score, Trabecular Bone Score-TBS and Bone Strain Index-BSI at Lumbar spine) and body composition data (Total Body DXA scans) were collected. Disease severity was defined according to Birmingham Epidermolysis Bullosa Severity (BEBS) score. RESULTS: Twenty-one patients (12 Recessive Dystrophic EB-RDEB, 3 Dominant Dystrophic EB, 3 Junctional EB-JEB, 2 EB Simplex and one Kindler EB) aged 13 years (females) or 14 years (males) and above were enrolled (age 16.2±2.5 years, M/F 11/10). Short stature was highly prevalent (57%, mean height -2.12±2.05 SDS) with 55% patients with height <-2SD their mid-parental height. 7/21 patients (33%, 6 RDEB and 1 JEB) had delayed puberty with a median BEBS of 50 (range 29 to 63), a height SDS of -2.59 SDS (range -5.95 to -2.22) and a median lumbar BMAD Z-score of -4.0 SDS (range -5.42 to -0.63 SDS). Pubertal status was negatively associated with BEBS, skin involvement, inflammatory state and positively with height SDS and BMI SDS. CONCLUSIONS: Pubertal delay is highly prevalent in EB, especially in patients with RDEB and JEB, high severity score and inflammatory state. Moreover, pubertal delay worsens growth impairment and bone health. A study on pubertal induction is ongoing to enlighten possible beneficial effects on adult height attainment and peak bone mass accrual.

A nutrition-based approach to epidermolysis bullosa: Causes, assessments, requirements and management.

Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of rare diseases characterized by skin and mucous membrane fragility. EB primarily involves the skin and, in specific subtypes, the mucous membrane, resulting in complications which can strongly affect nutritional status (e.g. gastrointestinal complications, hand deformities, pain). The aims of nutritional support mainly include improving nutritional status, alleviating the stress of oral feeding and minimizing nutritional deficiencies, thus consequently improving growth, pubertal development, bowel function, immune status and wound healing. The aim of this review is to discuss knowledge of different aspects of the disease related to nutrition and growth.

Impaired glucose metabolism in subjects with the Williams-Beuren syndrome: A five-year follow-up cohort study.

OBJECTIVE: The Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of ß-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults. METHODS: This observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity. RESULTS: IGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM. CONCLUSIONS: IGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and ß-cell dysfunction contribute, in this sequence, to progression to IGM and DM.

Nutritional Challenges in Duchenne Muscular Dystrophy.

Neuromuscular diseases (NMDs) represent a heterogeneous group of acquired or inherited conditions. Nutritional complications are frequent in NMDs, but they are sometimes underestimated. With the prolongation of survival in patients with NMDs, there are several nutritional aspects that are important to consider, including the deleterious effects of overnutrition on glucose metabolism, mobility, and respiratory and cardiologic functions; the impact of hyponutrition on muscle and ventilatory function; constipation and other gastrointestinal complications; chewing/swallowing difficulties with an increased risk of aspiration that predisposes to infectious diseases and respiratory complications; as well as osteoporosis with an associated increased risk of fractures. The aim of this review is to provide a comprehensive analysis of the nutritional aspects and complications that can start in children with Duchenne muscular dystrophy (DMD) and increase with ageing. These aspects should be considered in the transition from paediatric clinics to adult services. It is shown that appropriate nutritional care can help to improve the quality of life of DMD patients, and a multidisciplinary team is needed to support nutrition challenges in DMD patients. However, studies on the prevalence of overnutrition and undernutrition, gastrointestinal complications, infectious diseases, dysphagia, and reduced bone mass in the different types of NMDs are needed, and appropriate percentiles of weight, height, body mass index, and body composition appear to be extremely important to improve the management of patients with NMD.

Homocysteine metabolism in children and adolescents with epidermolysis bullosa.

BACKGROUND: Epidermolysis bullosa (EB) belongs to a family of rare heterogeneous, genetic disorders characterized by blistering of the skin and mucous membranes in response to minor mechanical trauma. The involvement of the oral mucosa and oesophagus stenosis is suggested to be responsible for severe nutritional deficiencies, but few studies have till now considered this aspect. This observational study aimed to evaluate homocysteine status in children and adolescents with EB by assessing total plasma homocysteine (tHcy) and metabolically related vitamins (B6, B12, folate) concentrations. METHODS: Twenty EB patients (12 M; age range 0.5-19 years) were evaluated for: plasma tHcy, serum B12 and holotranscobalamin (HoloTC, the active fraction of B12), serum and erythrocyte folate (s-F and Ery-F, respectively), plasma B6 and serum high sensitive C-reactive-protein (hsCRP) levels. Clinical severity was also evaluated through the Birmingham Epidermolysis Bullosa Severity (BEBS) score. A sex and age well-matched population was also enrolled. RESULTS: EB patients showed tHcy levels higher (p = 0.04) and B6 levels lower (p = 0.03) than controls. B12, HoloTC, s-F and ery-F concentrations did not differ between patients and controls. Multiple linear regression analysis showed that tHcy levels were independent of the metabolically related vitamins levels. In addition, serum hsCRP levels were higher in EB patients than in controls (p = 0.003) and correlated negatively with B6 concentrations (r = -0.6; p = 0.009). BEBS score correlated negatively with HoloTC (p = 0.022) and B6 (p = 0.005) levels and positively with age (p = 0.031) and hsCRP levels (p < 0.001). CONCLUSIONS: The assessment of tHcy and metabolically related vitamin levels describes an important aspect of EB patients' nutritional status which can result essential for their long term care. Monitoring B6 levels in EB patients could be particularly important in order to prevent several complications associated with B6 deficiency and to avoid a B6 excess which sustains an inflammatory condition.

Oral viscous budesonide as a first-line approach to esophageal stenosis in epidermolysis bullosa: an open-label trial in six children.

BACKGROUND: Esophageal and pharyngeal problems are common in the majority of patients with epidermolysis bullosa (EB). Repeated blister formation and ulceration, coupled with chronic inflammation, result in scarring and development of esophageal strictures. OBJECTIVE: This study aimed to evaluate whether oral viscous budesonide (OVB) was useful for treating esophageal structures in six pediatric patients (aged 8-17 years) with EB who were affected by dysphagia and esophageal strictures. METHODS: Patients were treated for 4 months with twice-daily oral budesonide nebulizer solution 0.5 mg/2 mL mixed with maltodextrin 5 g and artificial sweeteners. RESULTS: One patient developed a severe oral mycotic infection and discontinued treatment. The other five patients completed the treatment regimen and displayed significantly lower stricture indices (SIs) post-treatment (mean SI ± standard deviation 0.736 ± 0.101 pre-treatment versus 0.558 ± 0.162 post-treatment; p = 0.008). Patients experienced a mean SI decrease of 0.178 (range 0.026-0.296), as well as improved dietary habits in the absence of side effects. CONCLUSION: These findings indicated that topical corticosteroids may significantly alleviate strictures in pediatric patients with EB, thereby limiting the need for endoscopic dilation and considerably improving patients' quality of life.

Intradialytic cycling in children and young adults on chronic hemodialysis.

BACKGROUND: Intradialytic exercise has been poorly investigated in pediatric patients on chronic hemodialysis (HD). The aim of this study was to assess the acceptability, safety and efficacy of intradialytic exercise in children and young adults on HD. METHODS: The intradialytic exercise program consisted of 30-min sessions of intra-HD exercise using a cycloergometer two to three times a week for 3 months. Study endpoints were the 6-min walking test (6MWT) distances, lung function, number of stands in the chair test, lower extremity strength (LES), anthropometry, dietary intake, dialysis adequacy, incidence of symptomatic sessions, biochemistry and left ventricular mass index. RESULTS: Ten pediatric patients with a median age of 15.3 (range 9.1-24.2) years were enrolled. Two of these underwent kidney transplantation; the remaining eight completed the study and adapted well to the exercise program. At the end of the 3-month study period, all patients had significantly improved results for the 6MWT (+4.9 %; p < 0.05), chair test (+19 %; p < 0.05) and LES (+29.3 %; p < 0.05). Pre-HD albumin, creatinine and total protein levels and post-HD creatinine levels had also significantly improved. The incidence of symptomatic sessions did not increase during the study period. No adverse events occurred. CONCLUSIONS: Based on our results, we conclude that a 30-min exercise program of intradialytic cycling is feasible for the majority of pediatric patients on chronic HD and will be well accepted. Such an exercise program can lead to a significant improvement in the exercise capacity of this patient population.

Correlates of exercise capacity in pediatric patients on chronic hemodialysis.

OBJECTIVE: Pediatric patients on chronic hemodialysis (HD) are at high risk of inactivity and poor physical fitness. The aim of this study was to assess the main correlates of exercise capacity in a cohort of children and young adults on chronic HD. METHODS: Twelve patients on chronic HD (median age 15.6 years; range 9.1-24.2) underwent a 6-minute walking test (WT), spirometry, a 1-minute chair stand test, and the measurement of lower extremity strength. Demographic data, anthropometry (dry weight, height, body mass index, and skinfold thickness, all expressed as standard deviation scores [SDS]), biochemistry (serum albumin, hemoglobin, creatinine, C-reactive protein, bicarbonate), bioimpedance analysis, HD adequacy indices (spKt/V and eKt/V), left ventricular mass index, and medications were also recorded. RESULTS: There was a significant correlation among the distance covered during the WT (median 552 m, range 186-670), forced vital capacity (87.8% of predicted, range 49.7-136), forced expiratory volume in 1 second (86.7%, range 54.7-126.7), and peak expiratory flow (75.5%, 49.7-105.1). All of these indices positively correlated with the weight SDS (r 0.69-0.85), pre-HD serum creatinine (0.57-0.77), and serum albumin (0.60-0.77) and negatively correlated with weekly erythropoietin dose per kilogram of body weight (from -0.64 to -0.83), with P values ranging from <.05 to <.0005. Lower extremity strength (median 11.5 kg, range 3-15) positively correlated with the number of stands at the chair stand test (median 33, range 18-47; r 0.73, P < .05) and serum albumin (r 0.83, P < .01). Distance at the WT, forced vital capacity, lower extremity strength, and the number of stands at the chair stand test all negatively correlated with C-reactive protein levels (r from -0.81 to -0.67, P < .05). CONCLUSION: Our findings show that protein-energy wasting and chronic inflammation are strongly correlated with the exercise capacity of children and young adults on chronic HD.

Severe vitamin B12 deficiency in an exclusively breastfed 5-month-old Italian infant born to a mother receiving multivitamin supplementation during pregnancy.

BACKGROUND: In infants, vitamin B12 deficiency may be due to an inborn error of absorption and metabolism, or nutritional problems. CASE PRESENTATION: An exclusively breastfed 5-month-old Italian male infant, who was born after a normal full-term pregnancy to a vegan mother who was apparently daily treated with a multivitamin oral preparation during the second and third trimester, was hospitalised because of poor weight gain, feeding difficulties, severe pallor, muscle hypotonia and somnolence. Upon admission, his weight, length and head circumference were below the third percentile, he had an enlarged liver and spleen, and showed a significant delay in developmental milestones and communicative reactions. He had a hemoglobin level of 4.7 g/dL with an MCV of 84.2 fL, a white blood cell count of 4,680/mm3, and a platelet count of 45,000/mm3. His serum vitamin B12 level was 57 pg/mL (normal value 180-500 pg/mL) and serum folate level 12.8 ng/mL (normal value >3 ng/mL). The results of metabolic examinations excluded a cobalamin C disorder, whereas nutritional screening showed a serum iron concentration of 9 µg/dL and serum ferritin of 4 ng/mL. Magnetic resonance imaging of the brain showed mild dilatation of the lateral ventricles with diffuse delayed myelination. The child was diagnosed as having vitamin B12 and iron deficiency due to nutritional inadequacy and was immediately treated with packed red blood cells, intramuscular vitamin B12 injections, and iron supplementation. A few days after the start of therapy, his hemoglobin levels and other hematological parameters rapidly improved, and a clinical improvement was observed within few weeks. There was an increase in his achievement of developmental milestones, but his development was still retarded seven months after the start of therapy. CONCLUSION: This case underlines the importance of adequately controlling maternal vitamin B12 intake during pregnancy by means of supplementation which, in the case of vegan mothers, should be significantly greater than that usually given. Moreover, the supplementation should be continued during lactation in order to avoid the development of signs of deficiency that may be associated with persistent neurological problems in infants. The case also highlights the need to consider vitamin B12 deficiency in infants with severe anemia even if their hematological parameters do not indicate megaloblastic anemia because the concomitant presence of substantial iron deficiency may modify the characteristics of the anemia.