Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

Increased parental perception of sleep disordered breathing in a cohort of infants with ALTE/BRUE events.

BACKGROUND: An apparent life-threatening event (ALTE) describes an acute, unexpected change in an infant's breathing, aspect, or behavior frightening to the parent or caretaker. According to the new recent terminology, clinicians should use the term brief resolved unexplained event (BRUE) to describe an event occurring in an infant <1 year of age when the observer reports a sudden, brief, and now resolved episode. The aims of the present study in infants were to investigate sleep disturbances in both ALTE event and after their classification according the new BRUE criteria. METHODS: We enrolled (from April to May 2016) 32 consecutive infants referred to our ambulatory for sleep disorders for follow-up after an ALTE episode and 32 pair healthy controls. We administered to parents the adapted questionnaire "Sleep Disturbance Scale for Children - SDSC." RESULTS: Among enrolled infants with ALTE, there were 26 infants in line with the new BRUE definition, of which 10 at low risk and 16 at the high-risk event. CONCLUSIONS: Infants with ALTE and BRUE had more referred-by-parents' sleep symptoms than controls. In particular, sleep disordered breathing wa prevalent in both, requiring a longer follow-up for this disturbance.

Tissue sensitivity to thyroid hormones may change over time.

INTRODUCTION: Patients with congenital hypothyroidism (CH) may transiently show a certain degree of pituitary resistance to levothyroxine (LT4) which, however, normalizes subsequently. However, in some individuals, thyroid-stimulating hormone (TSH) fails to normalize despite adequate LT4 treatment. METHODS: Nine patients with CH followed in three Academic Centre who developed over time resistance to thyroid hormones underwent extensive biochemical and genetic analyses. These latter were performed by Sanger sequence or targeted next-generation sequencing technique including a panel of candidate genes involved in thyroid hormone actions and congenital hypothyroidism (CH): THRA, THRB, DIO1, DIO2, SLC16A2, SECISBP2, DUOX2, DUOXA2, FOXE1, GLIS3, IYD, JAG1, NKX2-1, NKX2- 5, PAX8, SLC26A4, SLC5A5, TG, TPO, TSHR. RESULTS: All patients displayed a normal sensitivity to thyroid hormone (TH) in the first years of life but developed variable degrees of resistance to LT4 treatment at later stages. In all cases, TSH normalized only in the presence of high free thyroxine levels. Tri-iodothyronine suppression test followed by thyrotrophin-releasing hormone stimulation was performed in two cases and was compatible with central resistance to THs. This biochemical feature was present independently on the cause of CH, being observed either in patients with an ectopic (n = 2) or eutopic gland (n = 3) or in case of athyreosis (n = 1). None of the patients had genetic variants in genes involved in the regulation of TH actions, while in two cases, we found two double heterozygous missense variants in TSHR and GLIS3 or in DUOX2 and SLC26A4 genes, respectively. CONCLUSIONS: We report CH patients who showed an acquired and unexplainable pituitary refractoriness to TH action.

Decreasing prevalence of retinopathy in childhood-onset type 1 diabetes over the last decade: A comparison of two cohorts diagnosed 10 years apart.

AIM: To ascertain whether the prevalence of retinopathy has declined over the last 2 decades in individuals with childhood-onset type 1 diabetes and whether this might be explained by changes in lifetime HbA1c. MATERIALS AND METHODS: A multicentre, retrospective, observational study, comparing 128 subjects with diabetes onset in 2000-2003 assessed for retinopathy in 2016-2019, with a previous cohort of 115 individuals diagnosed in 1990-1993 and assessed for retinopathy in 2007-2009, was conducted. The two cohorts had both a similar diabetes duration and age at diagnosis. Retinal photographs were centrally graded. Lifetime HbA1c and its variability, estimated as the ratio between intrapersonal mean and standard deviation of HbA1c, were evaluated. RESULTS: The prevalence of any retinopathy in the new and old cohort was 24.2% and 43.5% (P < .003), respectively, and that of severe retinopathy was 1.7% and 9.6% (P = .018). Lifetime HbA1c was lower in the new cohort (7.8% ± 0.8% vs. 8.1% ± 0.8%; P = .002) during all periods following the first 5 years after diagnosis. Patients without retinopathy in the two cohorts had similar levels of HbA1c. Compared with patients without retinopathy, those with retinopathy had higher lifetime HbA1c and long-term HbA1c variability. However, on multiple regression analysis, only lifetime HbA1c was independently associated with retinopathy (P = .0018). CONCLUSIONS: The risk of developing retinopathy was nearly halved in children who developed type 1 diabetes in the new millennium compared with previous cohorts. These results confirm that maintaining the lowest possible levels of HbA1c throughout lifetime protects from diabetic retinopathy.

Benefits of multidisciplinary care in Prader-Willi syndrome.

Introduction: Prader-Willi syndrome (PWS) is the most well-known condition of genetic obesity. Over the past 20 years, advances have been achieved in the diagnosis and treatment of PWS with a significant improvement in prognosis.Areas covered: This review focuses on the benefits of multidisciplinary approach in children and adolescents with PWS. In particular, the neonatologist and geneticist play a key role in early diagnosis and the clinical follow-up of the PWS patient must be guaranteed by a team including pediatric endocrinologist, psychologist, nutritionist/dietician, neurologist/neuropsychiatrist, sleep specialist, ears, nose and throat specialist (ENT), lung specialist, dentist, orthopedist and ophthalmologist and, eventually, gastroenterologist. We searched PubMed and critically summarized what has been reported in the last 10 years on PWS.Expert opinion: The multidisciplinary care in association with an early diagnosis and GH treatment postpones overweight development and decreases prevalence of obesity in individuals with PWS. Further prognostic improvements are expected through the selection of teams particularly experienced in the management of individuals with PWS and the discovery of new drugs.

Uniparental disomy and pretreatment IGF-1 may predict elevated IGF-1 levels in Prader-Willi patients on GH treatment.

Pediatric patients with Prader-Willi syndrome (PWS) can be treated with recombinant human GH (rhGH). These patients are highly sensitive to rhGH and the standard doses suggested by the international guidelines often result in IGF-1 above the normal range. We aimed to evaluate 1 the proper rhGH dose to optimize auxological outcomes and to avoid potential overtreatment, and 2 which patients are more sensitive to rhGH. In this multicenter real-life study, we recruited 215 patients with PWS older than 1 year, on rhGH at least for 6 months, from Italian Centers for PWS care. We collected auxological parameters, rhGH dose, IGF-1 at recruitment and (when available) at start of treatment. The rhGH dose was 4.3 (0.7/8.4) mg/m2/week. At recruitment, IGF-1 was normal in 72.1% and elevated in 27.9% of the patients. In the group of 115 patients with IGF-1 available at start of rhGH, normal pretreatment IGF-1 and uniparental disomy were associated with elevated IGF-1 during the therapy. No difference in height and growth velocity was found between patients treated with the highest and the lowest range dose. The rhGH dose prescribed in Italy seems lower than the recommended one. Normal pretreatment IGF-1 and uniparental disomy are risk factors for elevated IGF-1. The latter seems to be associated with higher sensitivity to GH. In case of these risk factors, we recommend a more accurate titration of the dose to avoid overtreatment and its potential side effects.

Subcutaneous Immunoglobulin in Infantile Chronic Inflammatory Demyelinating Polyneuropathy: A Case Report.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronically progressive or relapsing sensorimotor disorder presumably due to antibody-mediated reactions. It is a rare condition in children, with estimated prevalence as 0.48 per 100,000 among patients younger than 20 years of age. Recommended treatments include immune modulators, intravenous immunoglobulins (IVIgs), steroids, and plasmapheresis. Management of pediatric CIDP is challenging because of the lack of evidence-based efficacy of the current therapies in children. Because of the rarity of this condition, there are no double-blind randomized studies to support the therapeutic choice as well as to identify the optimal first-line therapeutic regimen. IVIgs are widely used but the intravenous administration is usually uncomfortable, especially for children. Subcutaneous immunoglobulins (SCIgs) have proven to be effective in adults with CIDP and in children affected by antibody deficiencies and other different immune and inflammatory disorders. Herein, we described the case of a 7-year-old boy, affected by CIDP who clinically responded to IVIg but was dependent on this therapy. In order to improve his quality of life, we switched to SCIg with excellent result.

Anthropometric characteristics of newborns with Prader-Willi syndrome.

This is a retrospective multicenter nationwide Italian study collecting neonatal anthropometric data of Caucasian subjects with Prader-Willi syndrome (PWS) born from 1988 to 2018. The aim of the study is to provide percentile charts for weight and length of singletons with PWS born between 36 and 42 gestational weeks. We collected the birth weight and birth length of 252 male and 244 female singleton live born infants with both parents of Italian origin and PWS genetically confirmed. Percentile smoothed curves of birth weight and length for gestational age were built through Cole's lambda, mu, sigma method. The data were compared to normal Italian standards. Newborns with PWS showed a lower mean birth weight, by 1/2 kg, and a shorter mean birth length, by 1 cm, than healthy neonates. Females with a 15q11-13 deletion were shorter than those with maternal uniparental maternal disomy of chromosome 15 (p < .0001). The present growth curves may be useful as further traits in supporting a suspicion of PWS in a newborn. Because impaired prenatal growth increases risk of health problems later in life, having neonatal anthropometric standards could be helpful to evaluate possible correlations between the presence or absence of small gestational age and some clinical and metabolic aspects of PWS.

Thyroid function in patients with Prader-Willi syndrome: an Italian multicenter study of 339 patients.

Background Prader-Willi syndrome (PWS) is a genetic disorder due to loss of expression of paternally transcribed genes of the imprinted region of chromosome 15q11-13. PWS is characterized by peculiar signs and symptoms and many endocrine abnormalities have been described (growth hormone deficiency, hypogonadotropic hypogonadism). The abnormalities of thyroid function are discussed in literature and published data are discordant. The aim of our study was to report the thyroid function in patients with PWS to identify the prevalence of thyroid dysfunction. Methods Thyroid function tests were carried out in 339 patients with PWS, aged from 0.2 to 50 years. A database was created to collect personal data, anthropometric data, thyroid function data and possible replacement therapy with L-thyroxine. Subjects were classified according to thyroid function as: euthyroidism (EuT), congenital hypothyroidism (C-HT), hypothyroidism (HT - high thyroid-stimulating hormone [TSH] and low free thyroxine [fT4]), central hypothyroidism (CE-H - low/normal TSH and low fT4), subclinical hypothyroidism (SH - high TSH and normal fT4), and hyperthyroidism (HyperT - low TSH and high fT4). Results Two hundred and forty-three out of 339 PWS patients were younger than 18 years (71.7%). The prevalence of thyroid dysfunction was 13.6%. Specifically, C-HT was found in four children (1.18%), HT in six patients (1.77%), CE-H in 23 patients (6.78%), SH in 13 patients (3.83%), and HyperT in none. All other subjects were in EuT (86.4%). Conclusions Hypothyroidism is a frequent feature in subjects with PWS. Thyroid function should be regularly investigated in all PWS patients both at the diagnosis and annually during follow-up.

Pediatric Dehydration Assessment at Triage: Prospective Study on Refilling Time.

PURPOSE: Dehydration is a paediatric medical emergency but there is no single standard parameter to evaluate it at the emergency department. Our aim was to evaluate the reliability and validity of capillary refilling time as a triage parameter to assess dehydration in children. METHODS: This was a prospective pilot cohort study of children who presented to two paediatric emergency departments in Italy, with symptoms of dehydration. Reliability was assessed by comparing the triage nurse's measurements with those obtained by the physician. Validity was demonstrated by using 6 parameters suggestive of dehydration. Comparison between refilling time (RT) and a validated Clinical Dehydration Score (CDS) was also considered. The scale's discriminative ability was evaluated for the outcome of starting intravenous rehydration therapy by using a receiver operating characteristic (ROC) curve. RESULTS: Participants were 242 children. All nurses found easy to elicit the RT after being trained. Interobserver reliability was fair, with a Cohen's kappa of 0.56 (95% confidence interval [CI], 0.41 to 0.70). There was a significant correlation between RT and weight loss percentage (r-squared=-0.27; 95% CI, -0.47 to -0.04). The scale's discriminative ability yielded an area under the ROC curve (AUC) of 0.65 (95% CI, 0.57 to 0.73). We found a similarity between RT AUC and CDS-scale AUC matching the two ROC curves. CONCLUSION: The study showed that RT represents a fast and handy tool to recognize dehydrated children who need a prompt rehydration and may be introduced in the triage line-up.

The Effect of Alginate in Gastroesophageal Reflux in Infants.

BACKGROUND: Guidelines are contradictory regarding the use of alginate in infants with persisting gastroesophageal reflux (GER). While The British National Institute for Health and Care (NICE) guidelines consider alginate as a treatment option, the guidelines of the European and North-American Societies for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN, NASPGHAN) do not recommend alginates. AIMS: We assessed the efficacy of alginate to reduce GER episodes in infants. METHODS: In a prospective, observational study, we consecutively enrolled all infants referred for pH-multiple intraluminal impedance (pH-MII) recording because of persisting GER symptoms not responsive to behavior and dietetic modifications. A 48-h pH-MII was performed in all infants; a baseline recording was performed during the first 24 h while magnesium or sodium alginate was administered during the second 24 h. The primary endpoint was the difference in the total number of GER episodes per 24 h between the baseline day and the second day during which the alginate was administered. The secondary outcome was the difference in symptoms between each period. We also compared other pH-MII data from before and during alginate administration. RESULTS: We recruited 43 infants (median age 68 days, range 25-306); three pH-MII tracings were excluded because of artifacts. The median number of all MII reflux episodes was significantly reduced during alginate administration (76.0 vs 69.5; p < 0.001). Crying-fussiness, cough and regurgitation episodes all significantly improved during alginate administration (p = 0.00012; p = 0.005 and p = 0.04, respectively). The following MII parameters also decreased during the alginate administration: acid (19.0 vs 14.5; p < 0.04), non-acid (52.0 vs 49.5; p < 0.004), proximal GER episodes (46.0 vs 41.4; p < 0.007), and bolus exposure index (1.9 vs 1.6; p = 0.002). At least three out of seven pH-MII parameters decreased by > 10% during the alginate period in 31/40 infants (77.5%), without a significant difference between magnesium and sodium alginate. CONCLUSION: These results suggest that alginate significantly decreases the number and extension of both acid and non-acid reflux episodes and associated symptoms in infants.

Ocular Manifestations of Paediatric Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Ocular extraintestinal manifestations [O-EIMs] are known complications of Crohn's disease [CD], ulcerative colitis [UC], and inflammatory bowel disease unclassified [IBD-U]. However, data on their prevalence in children are scarce and there are no clear recommendations on what follow-up should be offered. We aimed to review available data on O-EIMs in children. METHODS: In January 2018, we performed a systematic review of published English literature using PubMed and EMBASE databases and disease-specific queries. RESULTS: Fifteen studies [7467 patients] reported data on O-EIMs prevalence in children. Overall prevalence of O-EIMs was 0.62-1.82%. Uveitis was the most common O-EIM. Meta-analysis showed that children with CD are at increased risk of O-EIMs as compared with children with UC and IBD-U (odds ratio [OR] 2.70, 95% confidence interval [CI] 1.51-4.83). Five studies [357 patients] reported data on ophthalmological screening in asymptomatic children: mild asymptomatic uveitis was identified in a variable proportion of patients [1.06-23.1%], more frequently in male patients with CD and colonic involvement. No evidence of ocular complications from untreated uveitis was detected. A total of 23 case reports [24 patients] were identified. CONCLUSIONS: Data on O-EIMs in children are scarce. Prevalence of O-EIMs is lower than in adults but may be underestimated because of the possibility of asymptomatic uveitis; however, the long-term significance of this condition is unknown. Children with CD may be at increased risk of O-EIMs. No recommendations on routine ophthalmological examination can be made, but a low threshold for ophthalmological referral should be maintained. Larger studies in paediatric IBD populations are needed.

Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents.

At the time of the clinical onset of type 1 diabetes (T1D), we investigated 82 pediatric cases in parallel with 117 non-diabetic controls matched by age, geographic area, and time of collection. The occurrence of an enteroviral infection was evaluated in peripheral blood using a sensitive method capable of detecting virtually all human enterovirus (EV) types. While non-diabetic controls were consistently EV-negative, 65% of T1D cases carried EVs in blood. The vitamin D status was assessed by measuring the concentration of 25-hydroxyvitamin D [25(OH)D] in serum. Levels of 25(OH)D were interpreted as deficiency (≤50 nmol/L), insufficiency (52.5-72.5 nmol/L), and sufficiency (75-250 nmol/L). In T1D cases, the median serum concentration of 25(OH)D was 54.4 ± 27.3 nmol/L vs 74.1 ± 28.5 nmol/L in controls (P = .0001). Diabetic children/adolescents showed deficient levels of vitamin D 25(OH)D (ie, 72.5 nmol/L) in 48.8% cases vs 17.9% in non-diabetic controls (P = .0001). Unexpectedly, the median vitamin D concentration was significantly reduced in virus-positive vs virus-negative diabetics (48.2 ± 22.5 vs 61.8 ± 31.2 nmol/L; P = .015), with deficient levels in 58.5% vs 31.0%, respectively. Thus, at the time of clinical onset, EV-positive cases had reduced vitamin D levels compared with EV-negative cases. This could indicate either that the virus-negative children/adolescents had been hit by a non-infectious T1D-triggering event, or that children/adolescents with proper levels of vitamin D had been able to rapidly clear the virus. Thus, it would be important to assess whether adequate vitamin D supplementation before or during the prediabetic phase of T1D may counteract the diabetogenic potential of infectious pathogens.

Pediatric GIST presenting as anemia.

Gastrointestinal stromal tumors (GIST) are tumors of the gastrointestinal (GI) tract originating from the myenteric ganglion cells (interstitial cells of Cajal), that are very rare in children and adolescents. The most common clinical manifestation is acute or chronic, overt or occult GI bleeding although these tumors are asymptomatic in 10-30% of patients. We report a case of gastric GIST in a 11-year-old girl presenting with an iron deficiency refractory anemia without gastrointestinal symptoms and stool evidence of GI bleeding that caused a slight diagnostic delay.

Revealing enterovirus infection in chronic human disorders: An integrated diagnostic approach.

Enteroviruses (EVs) causing persisting infection are characterized by minimal replication and genetic changes. Typing of these agents may complement disease assessment and shed light on pathogenesis. Here we report an integrated approach for EV detection in human samples that is based on pre-enrichment of virus in cell culture before search for the viral genome and viral antigens. Cases of post-polio syndrome, type 1 diabetes, and chronic cardiomyopathy were investigated. As tissue-based approaches require invasive procedures, information was mainly gleaned from virus in blood. Molecular assays targeting conserved genome regions of all EV types (5'UTR, 2 C, 3Dpol) were employed. As compared to direct assays of plasma or leukocytes, the EV detection rate was significantly enhanced by co-culture of leukocytes with cell lines prior to molecular and immunologic tests. Results of RT-PCR and sequencing were confirmed by staining cell cultures with a panel of EV-specific antibodies. Sequence and phylogenetic analysis showed that EVs of the C species (polioviruses) were associated with the post-polio syndrome, while members of the B species were found in type 1 diabetes and cardiomyopathy. The procedure may be used for investigating the possible association of different EVs with a variety of chronic neurologic, endocrine, and cardiac disorders.

Whole lipid profile and not only HDL cholesterol is impaired in children with coexisting type 1 diabetes and untreated celiac disease.

AIMS: Low HDL cholesterol (HDL-C) levels have been described in patients with coexisting type 1 diabetes mellitus (T1DM) and celiac disease (CD). Data on other possible lipid abnormalities that could further increase cardiovascular risk in these patients are scarce and incomplete. Aim of this retrospective multicenter study was to evaluate whole lipid profiles, besides HDL-C, in children with T1DM associated with biopsy-proven CD, and to investigate the influence of age and degree of adherence to gluten-free diet (GFD) on lipid changes. METHODS: A total of 261 children with both T1DM and CD were enrolled. Serum lipid profiles at CD diagnosis were compared with those after 1 year of GFD and with those of 224 matched children with T1DM alone. The adherence to GFD was judged by means of CD-related antibodies. RESULTS: At CD diagnosis, children with T1DM + CD showed higher LDL cholesterol (LDL-C) compared to children with T1DM alone. Gluten withdrawal failed to normalize LDL-C levels, not even in completely adherent individuals. HbA1c values were not influenced by GFD. The youngest children were characterized at diagnosis by lower levels of total cholesterol and on treatment by a greater decrease in triglycerides levels. CONCLUSIONS: An unfavorable lipid profile, characterized not only by low HDL-C levels but also by high LDL-C values, may increase the risk of cardiovascular disease in children with T1DM and untreated CD. Therefore, a strict gluten-free diet is mandatory in these children, especially the youngest.

How Accurate Is a Single Cutpoint to Identify High Blood Pressure in Adolescents?

In 2007 the International Diabetes Federation (IDF) proposed single blood pressure (BP) cutpoints (systolic: ≥130 mm Hg and diastolic: ≥85 mm Hg) for the diagnosis of high blood pressure (HBP) in adolescents. Before this proposal, HBP had been defined as BP at or above the 95th percentile for age, sex, and height percentile (reference standard). In this study, we evaluated the risk for misclassification when using the IDF single-cutpoints criteria. We first applied the IDF criteria to a reconstructed population with the same age, sex, and height distribution as the population used to develop the reference standard. The proposed single cutpoints corresponded to percentiles from the 81.6th to 99.9th for systolic BP and from the 92.9th to 98.9th for diastolic BP in the reconstructed population. Using IDF criteria, there were high false-negative fractions for both systolic and diastolic BP (from 54% to 93%) in 10- to 12-year-olds and a false-positive fraction up to 35% in older subjects. We then applied the IDF criteria to 1,162 overweight/obese adolescents recruited during 1998-2000 from pediatric clinical centers in Milano, Varese, and Modena in Italy and in Zaragoza, Spain. Overall false-negative and false-positive fractions were 22% and 2%, respectively; negative predictive values were especially low for 10- to 12-year-old subjects. The use of IDF's single cutpoints carries a high risk of misclassification, mostly due to false negatives in younger subjects. The effort to simplify diagnosis could be overcome by the risk of undiagnosed HBP.

The role of socio-economic and clinical factors on HbA1c in children and adolescents with type 1 diabetes: an Italian multicentre survey.

OBJECTIVE: To identify the role of the family's socio-economic and clinical characteristics on metabolic control in children and adolescents with type 1 diabetes. METHODS: In this cross-sectional, multicentre study, 768 subjects with type 1 diabetes under 18 years of age were consecutively recruited from January 2008 to February 2009. Target condition was considered for HbA1c values <7.5% (<58 mmol/mol). A multiple correspondence analysis (MCA) was performed to analyze the association between the socio-economic and clinical characteristics of the participants. A logistic regression analysis was performed to identify factors associated with the subjects metabolic control. In both analyses, the family's socio-economic status was represented, measured by the Hollingshead Four-Factor Index of Social Status (SES) or by parental years of education. RESULTS: A total of 28.1% of subjects reached target HbA1c values. The MCA identified a strong association between at-target condition and several factors: high levels of SES or high levels of parental education, the use of the carbohydrate counting system, the use of insulin pumps, the use of the insulin delivery system over a short period of time, a normal body mass index. The logistic regression analysis showed that SES and the mother's years of education were significantly associated with the target condition [odds ratio (OR): 1.01, 95% confidence interval (CI): 1.01-1.03, p = 0.029; OR: 1.05, 95% CI: 1.01-1.10, p = 0.027, respectively). CONCLUSIONS: Personal, clinical, and family characteristics were found to be associated with HbA1c target. Their identification can be crucial in addressing strategies to optimize metabolic control and improve diabetes management.

Ketoacidosis at diagnosis in childhood-onset diabetes and the risk of retinopathy 20years later.

AIMS: To investigate on the relationship between severity of ketoacidosis, an important risk factor for C-peptide preservation, and long-term microvascular complications in childhood-onset type 1 diabetes mellitus (T1DM). METHODS: 230 childhood-onset diabetic patients (177 pre-pubertal), aged 7.0±3.8years followed for at least 15years after their diagnosis, were enrolled. Clinical and laboratory data at diagnosis, and C-peptide levels in a subset of patients, were compared with the severity of retinopathy and nephropathy, after a mean of 19.6±3.8years of disease. Digital retinal photographs were taken in all patients, and centrally graded. Repeated measurements of HbA1c and microalbuminuria for the whole duration of diabetes were collected in over half of the cases. RESULTS: Out of 230 patients, those with the lowest age at diagnosis had the most severe DKA and clinical conditions (p<0.05), and lower C-peptide levels (p<0.0001) at diagnosis. There was a significant relationship between pH and clinical severity (r=-0.783, p<0.0001), and between pH and C-peptide levels (r=0.278, p<0.05). The severity of ketoacidosis had no relationship with subsequent lifetime HbA1c values and long-term microvascular complications. In logistic regression analysis, the only variables that independently influenced severity of retinopathy were lifetime HbA1c (B=0.838, p<0.001), duration of disease (B=0.208, p<0.005) and age at diagnosis (B=0.116, p<0.05). CONCLUSIONS: The degree of metabolic derangement at diagnosis is not associated with retinopathy and nephropathy in childhood-onset T1DM. Age at diagnosis seems to be an important variable to be considered when evaluating the long-term effects of residual beta-cell function.