Renata Lorini

Wolfram syndrome: new mutations, different phenotype.

Background Wolfram Syndrome (WS) is an autosomal recessive neurodegenerative disorder characterized by Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness identified by the acronym “DIDMOAD”. The WS gene, WFS1, encodes a transmembrane protein called Wolframin, which recent evidence suggests may serve as a novel endoplasmic reticulum calcium channel in pancreatic β-cells and neurons. WS is a rare disease, with an estimated prevalence of 1/550.000 children, with a carrier frequency of 1/354. The aim of our study was to determine the genotype of WS patients in order to establish a genotype/phenotype correlation. Methodology/Principal Findings We clinically evaluated 9 young patients from 9 unrelated families (6 males, 3 females). Basic criteria for WS clinical diagnosis were coexistence of insulin-treated diabetes mellitus and optic atrophy occurring before 15 years of age. Genetic analysis for WFS1 was performed by direct sequencing. Molecular sequencing revealed 5 heterozygous compound and 3 homozygous mutations. All of them were located in exon 8, except one in exon 4. In one proband only an heterozygous mutation (A684V) was found. Two new variants c.2663 C>A and c.1381 A>C were detected. Conclusions/Significance Our study increases the spectrum of WFS1 mutations with two novel variants. The male patient carrying the compound mutation [c.1060_1062delTTC]+[c.2663 C>A] showed the most severe phenotype: diabetes mellitus, optic atrophy (visual acuity 5/10), deafness with deep auditory bilaterally 8000 Hz, diabetes insipidus associated to reduced volume of posterior pituitary and pons. He died in bed at the age of 13 years. The other patient carrying the compound mutation [c.409_424dup16]+[c.1381 A>C] showed a less severe phenotype (DM, OA).

The ALBA Project: an evaluation of needs, management, fears of Italian young patients with type 1 diabetes in a school setting and an evaluation of parents' and teachers' perceptions.

Pinelli L, Zaffani S, Cappa M, Carboniero V, Cerutti F, Cherubini V, Chiarelli F, Colombini MI, La Loggia A, Pisanti P, Vanelli M, Lorini R. The ALBA Project: an evaluation of needs, management, fears of Italian young patients with type 1 diabetes in a school setting and an evaluation of parents and teachers perceptions.

Long term persistence of anti-HBs protective levels in young patients with type 1 diabetes after recombinant hepatitis B vaccine.

The aim of the present study was to evaluate the persistence of anti-hepatitis B protective levels in young patients with type 1 diabetes, successfully immunised with a recombinant hepatitis B vaccine. We re-evaluated, after a 4 year follow-up, 54 patients and 70 age and sex-matched healthy subjects. Protective antibodies levels were found in 50/54 (92%) patients and in 67/70 (96%) controls. Moreover, anti-HBs levels were similar in diabetic patients and controls (means of log-titre and (sd); 1.95 (0.88) and 2.18 (0.64) patients and controls, respectively; P=0.11). No cases of clinical hepatitis were reported and all patients and controls remained HBc negative. These data demonstrate the persistence of anti-HBs levels in children, adolescents and young patients with type 1 diabetes after recombinant hepatitis B vaccine showing evidence of longterm immunogenity and protective effect.

Retinopathy screening in patients with type 1 diabetes diagnosed in young age using a non-mydriatic digital stereoscopic retinal imaging.

Background: Diabetic retinopathy seriously impairs patients’ quality of life, since it represents the first cause of blindness in industrialized countries. Aim: To estimate prevalence of retinopathy in young Type 1 diabetes patients using a non-mydriatic digital stereoscopic retinal imaging (NMDSRI), and to evaluate the impact of socio-demographic, clinical, and metabolic variables. Subjects and methods: In 247 young patients glycated hemoglobin (HbA1c), gender, age, pubertal stage, presence of diabetic ketoacidosis (DKA), HLA-DQ heterodimers of susceptibility for Type 1 diabetes, and β-cell autoimmunity at clinical onset were considered. At retinopathy screening, we evaluated age, disease duration, pubertal stage, body mass index (BMI-SDS), insulin requirement, HbA1c levels, other autoimmune diseases, diabetes-related complications, serum concentrations of cholesterol and triglycerides, systolic and diastolic blood pressure. Results: Retinopathy was found in 26/247patients: 25 showed background retinopathy, and 1 had a sight-threatening retinopathy. A significant relationship between retinopathy and female gender (p=0.01), duration of disease ≥15 yr (p<0.0001), serum triglycerides levels >65 mg/dl (p=0.012) and mean HbA1c ≥7.5% or >9% (p=0.0014) were found at the multivariate logistic analysis. Conclusions: Metabolic control is the most important modifiable factor and promotion of continuous educational process to reach a good metabolic control is a cornerstone to prevent microangiopathic complications. Symptoms appear when the complication is already established; a screening program with an early diagnosis is mandatory to prevent an irreversible damage.

Nationwide cross-sectional survey of 3560 children and adolescents with diabetes in Italy

Clinical characteristics and metabolic control in a large cohort of children with Type 1 diabetes (T1DM) were evaluated. Fifty-three Italian centers for childhood diabetes collected blood samples and clinical records from 3560 consecutive eligible patients aged 1.6–17.10 yr with disease duration >12 months. HbA1c determinations were centralized in a Diabetes Control and Complications Trial-controlled laboratory. HbA1c grand mean was 8.87±1.77%. Thirty-two percent of the patients had HbA1c values <8.0%. Puberty and disease duration were the main determinants of increase in HbA1c levels (<0.001 ). HbA1c values were inversely correlated to the frequency of blood glucose monitoring (p<0.001). Among the total population, 53.7% of the patients had 4 or more injections per day, 37.8% three injections, 7.4% ≤ 2 injections and only 1.1% was on pumps. Daily number of injections increased with age (p<0.001). Hypoglycemia episodes were reported in 17.6% patient-years and diabetic ketoacidosis (DKA) in 1.0% of children, more frequently in those with HbA1c >8.8% (p<0.02). Two thirds of Italian children with T1DM have HbA1c>8% despite regionalized centers, multidisciplinary team approach, free access to appropriate diabetes care, education, frequent blood glucose monitoring and multiple insulin injections.

Impact of inhaled corticosteroids on the risk of early Pseudomonas aeruginosa acquisition in cystic fibrosis.

Aim: To investigate the role of inhaled corticosteroids (IC) on the risk of Pseudomonas aeruginosa acquisition before the age of 10 y in cystic fibrosis (CF) patients. Methods: For each subject the cumulative dose kg‐1 of IC received for each year of age was calculated until the end of follow‐up. The age at CF diagnosis, the nutritional status (NS) and the number of respiratory exacerbations (RE) were used as surrogate measures for the severity of CF. Results: A total of 83 patients (40 M, 43 F) entered the study. Their median length of follow‐up was 4.4 y, for a total of 386 person‐years at risk. Twenty‐three patients acquired P. aeruginosa at a median age of 4.6 y (range 0.4‐9.9 y). The estimated survival without P. aeruginosa acquisition was 65% at 10 y of age. The effect of different risk factors (IC, NS, RE and age at CF diagnosis) on the probability of P. aeruginosa acquisition was evaluated: none of them was significantly associated with the risk of P. aeruginosa acquisition. In particular, patients receiving very high cumulative doses of IC (4th quartile) had a non‐significantly increased risk of P. aeruginosa acquisition compared with those receiving low doses of IC (1st quartile) (hazard ratio = 1.73, 95% confidence limits 0.40‐7.38).

May T1 diabetes mellitus protect from asthma

BACKGROUNDnType 1 diabetes mellitus (T1DM) may be associated with allergy. It was previously reported that >20% of children with T1DM had allergic rhinitis (AR), but none was asthmatic. This finding was surprising as allergic rhinitis is frequently associated with asthma and asthma prevalence is about 10% of the general paediatric population. Thus, it was hypothesized that T1DM could protect from asthma.nnnOBJECTIVESnThe aim of this preliminary study was to evaluate the pulmonary function and the response to bronchodilation testing in children, suffering from T1DM with associated AR, comparing them with a control group of children with AR alone.nnnMETHODSnTwenty children with T1DM and AR were compared with 59 children with AR alone; spirometry and bronchodilation testing were performed in all patients.nnnRESULTSnThere were no statistically significant differences in both at baseline and after bronchodilation testing about FVC, FEV1, and FEF25-75 values. However, changes in post-bronchodilator values of FEF25-75 (ΔFEF25-75) were significantly higher in children with AR alone than in children with T1DM and AR (p=0.04).nnnCONCLUSIONSnThis preliminary study could sustain the hypothesis that T1DM in children suffering also from AR might exert a protective effect of preventing the possible evolution in asthma.

Amyand’s hernia in a child with permanent neonatal diabetes due to pancreatic agenesis.

Acute or perforated appendicitis within inguinal hernia is rarely encountered and it is known as Amyands hernia. We report on the first case occurring in a 4-year-old boy affected by permanent neonatal diabetes mellitus due to pancreatic agenesis, an extremely rare condition. The initial suspicion of inguinal hernia was confirmed by ultrasound examination of the right inguinal region which revealed omental layers inside a swollen inguinal canal; this finding and the clinical presentation allowed a prompt and appropriate surgical management. The careful evaluation of this patient and early recognition of this unique presentation of appendicitis allowed trans-hernial appendectomy and immediate herniorrhaphy. Ultrasonography played a pivotal role to reach the correct diagnosis and to start a prompt treatment.

Absence of sonic hedgehog (Shh) germline mutations in patients with thyroid dysgenesis.

Thyroid dysgenesis accounts for 75% of all cases of CH, and includes thyroid agenesis or hemiagenesis, hypoplasia and ectopy. Although most cases of CH are sporadic, it has been estimate that up to 2% of cases of thyroid dysgenesis have a familial occurrence. 2 The development of the thyroid gland and its normal migration depends on the action of various thyroid transcription factors (TTF), such as TTF-1, TTF-2 and Pax-8. Indeed, mice knocked-out for these genes show a phenotype resembling human CH. In humans, germline mutations of TTF-1, TTF-2 and Pax-8 are associated with different complex syndromes including thyroid dysgenesis. However, mutations in these genes have been identified in very few CH cases 3–5 indicating that the pathogenesis of CH should include other unidentified or nonscreened genes. Sonic hedgehog (Shh; MIM#600725) is a secreted protein involved in several key events during embryogenesis of vertebrates, including left–right axis determination and organ development. 6,7 Germline mutations of SHH have been reported in holoprosencephaly (HPE), a rare congenital anomaly characterized by a highly variable clinical expression in affected families. Genetic deletion of SHH in murine model causes severe defects in the development of midline neural structures. Recent evidence indicates that Shh is expressed in cardiac bud and indirectly governs the symmetric bilobation of the thyroid during late organogenesis and could repress inappropriate thyroid differentiation in nonthyroid embryonic tissues. Accordingly, in SHH knockout mice, thyroid fails to divide into two lobes, but develops in a single unilateral mass and ectopic thyroid tissue buds from the presumptive trachea are also observed. 8

Diabetes mellitus after kidney transplantation in pediatric recipients

We read with great interest the paper by Greenspan et al. [1] on the increased incidence of post-transplant diabetes mellitus (PTDM) in kidney allograft recipients. The authors emphasize the central role of a firstand second-degree family history of type 2 diabetes mellitus (DM), use of tacrolimus in immunosuppressive therapy, and hyperglycemia in the first 2 weeks after transplantation as significant risk factors for PTDM. Eleven children (4 males, 7 females) were identified with PTDM in a retrospective review of 101 pediatric kidney allograft recipients (10.9%), referred to the G. Gaslini Institute, Genoa, Italy in the last 5 years. As in the study of Greenspan et al. [1] PTDM was clinically defined by a serum glucose level higher than 200 mg/dl on more than one occasion and the need for subcutaneous insulin therapy. The presentation of PTDM was asymptomatic hyperglycemia during routine laboratory evaluation in all patients. None presented diabetic ketoacidosis. No patient was on human growth hormone after transplantation. The mean age at the time of transplant for the 11 patients with PTDM was 16.78 years (range 8.34– 22.79 years). The mean age of controls was 15.00 years (range 2.8–23.1 years). The mean time from transplantation to diagnosis of PTDM was 5.6 months (range 0– 33 months). All subjects received glucocorticoids, with either cyclosporin (CsA) or tacrolimus, as part of their immunosuppressive regimen. Only 1 of the 11 patients with PTDM had parameters consistent with obesity (body mass index of 30.2 kg/m2 compared with a 50th percentile normal value of 21.38 kg/m2). Islet cell autoantibodies, such as insulin and anti-glutamic acid decarboxylase autoantibodies, were negative in all patients tested. A family history of type 2 diabetes was present in 8 of 11 PTDM patients (72.7%); 2 of 11 (18%) had a first-degree relative and 6 of 11 (54.5%) a second-degree relative with type 2 DM. The 11 PTDM patients were treated with three or four daily insulin injections; 6 of 11 patients remained on insulin therapy at 24 months post PTDM diagnosis (range 11–45 months), while in 5 of 11, insulin therapy was withdrawn after a mean of 4.6 months (range 2– 10 months). We confirmed that the immunosuppressive regimen had an effect on the risk for PTDM. In our cohort, the frequency of PTDM was higher in the group receiving tacrolimus compared with the group receiving CsA [8/30 (26.7%) vs. 3/71 (4.2%), respectively, P<0.001]. At the time of PTDM diagnosis, the patients in the tacrolimus group were receiving a mean dose of 0.22€0.09 mg/kg per day (range 0.08–0.35), with mean trough levels of 12.06€2.8 ng/ml (range 9.1–16.2). No difference was observed in the PTDM frequency according to the steroid load. According to present knowledge, the dose should not exceed 0.3 mg/kg per day and trough levels after the acute post-transplant phase should not exceed 8 ng/ml to prevent the development of diabetes. On the basis of the evidence regarding the role of tacrolimus in inducing PTDM, we agree with Greenspan et al. [1] that it would be advisable to routinely screen for glucose tolerance all children awaiting renal transplantaM. Cotellessa · L. Cresta · L. Minicucci · R. Lorini Department of Pediatrics, University of Genoa, Genoa, Italy