Update on Diabetes Mellitus and Glucose Metabolism Alterations in Prader-Willi Syndrome.

PURPOSE OF REVIEW: This review summarizes our current knowledge on type 2 diabetes mellitus (T2DM) and glucose metabolism alterations in Prader-Willi syndrome (PWS), the most common syndromic cause of obesity, and serves as a guide for future research and current best practice. RECENT FINDINGS: Diabetes occurs in 10-25% of PWS patients, usually in adulthood. Severe obesity is a significant risk factor for developing of T2DM in PWS. Paradoxically, despite severe obesity, a relative hypoinsulinemia, without the expected insulin resistance, is frequently observed in PWS. The majority of PWS subjects with T2DM are asymptomatic and diabetes-related complications are infrequent. Long-term growth hormone therapy does not adversely influence glucose homeostasis in all ages, if weight gain does not occur. Early intervention to prevent obesity and the regular monitoring of glucose levels are recommended in PWS subjects. However, further studies are required to better understand the physiopathological mechanisms of T2DM in these patients.

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.

The rehabilitation of children and adolescents with severe or medically complicated obesity: an ISPED expert opinion document.

Severe/medically complicated obesity in childhood, and particularly in adolescence, is a real disability that requires an intensive and continuous approach which should follow the procedures and schedule of rehabilitation medicine. Given the lack of a specific document focusing on children and adolescents, the Childhood Obesity Study Group set out to explore the available evidence for the treatment of severe or medically complicated obesity and to set standards tailored to the specific context of the Italian Health Service. Through a series of meetings and electronic communications, the writing committee (selected from members of the Study Group) selected the key issues, explored the literature and produced a draft document which was submitted to the other experts until the final synthesis was approved by the group. In brief, the following issues were involved: (1) definition and epidemiology; (2) identification of common goals designed to regain functional competence and limit the progression of metabolic and psychological complications; (3) a multi-professional team approach; (4) the care setting. This paper is an expert opinion document on the rehabilitation of severe and medically complicated obesity in children and adolescents produced by experts belonging to the Childhood Obesity Study Group of the Italian Society for Pediatric Endocrinology and Diabetology (ISPED).

Expression of PD-1 Molecule on Regulatory T Lymphocytes in Patients with Insulin-Dependent Diabetes Mellitus.

Type 1 diabetes is caused by autoreactive T cells that destroy pancreatic beta cells. Animal models suggested that a CD4⁺CD25⁺ population has a regulatory function capable of preventing activation and effector functions of autoreactive T cells. However, the role of CD4⁺CD25high T cells in autoimmunity and their molecular mechanisms remain the subject of investigation. We therefore evaluated T regulatory cell frequencies and their PD-1 expression in the peripheral blood of long-standing diabetics under basal conditions and after CD3/CD28 stimulation. Under basal conditions, the percentages of T regulatory cells were significantly higher while that of T effector cells were significantly lower in patients than in controls. The ratio of regulatory to effector T cells was higher in patients than that in controls, suggesting that T regulatory cells were functional in patients. Percentages of total PD-1⁺, PD-1low and PD-1high expressing T regulatory cells did not change in patients and in controls. After stimulation, a defect in T regulatory cell proliferation was observed in diabetics and the percentages of total PD-1⁺, PD-1low and PD-1high expressing cells were lower in patients. Our data suggest a defective activation of T regulatory cells in long-standing diabetics due to a lower expression of PD-1 on their surface.

Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies.

The pathogenesis of autoimmunity was derived from a complex interaction of genetic and environmental factors. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a rare autosomal recessive disease caused by mutations in the autoimmune regulator (AIRE) gene. AIRE gene variants and, in particular, heterozygous loss-of-function mutations were also discovered in organ-specific autoimmune disorders, possibly contributing to their etiopathogenesis. It was suggested that even predisposition to develop certain autoimmune conditions may be derived from AIRE gene polymorphisms including S278R and intronic IVS9+6 G>A. In this study we unravel the hypothesis on whether AIRE gene variants may predispose individuals to associated autoimmune conditions in 41 Italian patients affected by non-APECED autoimmune polyendocrinopathies. We could not detect any heterozygous mutations of the AIRE gene. Although a trend of association was observed, heterozygous polymorphisms S278R and IVS9+6 G>A were detected in patients without statistically significant prevalence than in controls. Their putative contribution to autoimmune polyendocrinopathies and their predictive value in clinical strategies of disease development could be unravelled by analysing a larger sample of diseased patients and healthy individuals.

Corrigendum: Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review.

[This corrects the article DOI: 10.3389/fendo.2023.1168648.].

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.

Deconvolution-based assessment of pituitary GH secretion stimulated with GHRH+arginine in Prader-Willi adults and obese controls.

OBJECTIVE: The assessment of GH deficiency in adult patients with Prader-Willi syndrome (PWS) has been previously assessed through the evaluation of quantitative parameters, such as the peak value of GH response to exogenous stimuli. A comprehensive description of the pattern of secretory response obtainable by deconvolution analysis is still lacking. The aim of our study was to characterize the time evolution of responses of PWS subjects compared with obese controls. DESIGN AND SUBJECTS: GH responsiveness was measured following the combined administration of GHRH+arginine to 65 PWS adults (24 males, 41 females) aged 18-41·2 years, and 17 age-, gender- and body mass index-matched obese controls. PWS subjects were analysed considering the stratification on different genotypes. MEASUREMENTS: GH response to GHRH+arginine was analysed in terms of peak values, standard area under the curves (AUCs), AUCs due to the stimulus, AUCs of the Instantaneous Secretion Rate signal and Secretion Response Analysis. RESULTS: In terms of both peak values and AUC, GH responses were statistically different between PWS UPD15 and PWS DEL15 subjects as well as between PWS UPD15 and obese controls. PWS subjects showed a lower and a more delayed GH response compared with obese controls. Moreover, PWS UPD15 subjects had the most delayed GH response. CONCLUSIONS: Our findings demonstrate that impaired GH secretion in PWS subjects compared with obese controls regards not only amplitude parameters such as peak value and AUC, but also the shape of the secretory response, which is more delayed, especially for UPD15 subjects.

Central adrenal insufficiency in young adults with Prader-Willi syndrome.

OBJECTIVE: A high prevalence (60%) of central adrenal insufficiency (CAI) has been reported in Prader-Willi syndrome (PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low-dose short synacthen test (LDSST). DESIGN: Basal cortisol and ACTH, and 30-min cortisol after the administration of 1 µg synacthen, were determined in 53 PWS adults (33 females). A peak cortisol value of ≥500 nmol/l was taken as normal. Hormonal profiles were analysed in relation to gender, genotype and phenotype. Deficient patients were retested by high-dose short synachten test (HDSST) or a repeat LDSST. RESULTS: Mean ± SD basal cortisol and ACTH were 336·6 ± 140·7 nmol/l and 4·4 ± 3·7 pmol/l respectively. Cortisol rose to 615·4 ± 135·0 nmol/l after LDSST. Eight (15·1%) patients had a peak cortisol response <500 nmol/l, with a lower mean ± SD (range) basal cortisol of 184·9 ± 32·0 (138·0-231·7) compared with 364·1 ± 136·6 (149·0-744·5) in normal responders (P < 0·001). Seven of the eight patients underwent retesting, with 4 (7·5%) showing persistent suboptimal responses. Basal and peak cortisol correlated in females (r = 0·781, P < 0·001). Logistic regression revealed that only female gender and baseline cortisol were predictors of cortisol peaks (adjusted R square 0·505). CONCLUSIONS: Although CAI can be part of the adult PWS phenotype, it has a lower prevalence (7·5%) than previously reported. Clinicians are advised to test PWS patient for CAI. Our study also shows that basal cortisol is closely correlated with adrenal response to stimulation, indicating that its measurement may be helpful in selecting patients for LDSST.

Peculiar genotypes of the autoimmune regulator gene in Italian patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome.

BACKGROUND: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is due to mutations in the autoimmune regulator gene (AIRE). The highest number of patients was reported in Finland and among other ethnic groups such as Iranian Jews. Hot spots of incidence are also in Italian regions including Sardinia, Apulia, and the Venetian region, where peculiar AIRE genotypes were identified. METHODS: We conducted screenings of all the 14 exons of the AIRE gene in 5 APECED patients from 3 different Italian regions. RESULTS: We confirmed the peculiar Sardinian R139X genotype in 2 Sardinians and unusually in one patient from the Venetian region. As expected, exon 1 mutation was detected in one patient from Campania, while the other with the novel c.1314-1326del13/insGT mutation in exon 11 and already described, presented candidiasis and autoimmune hepatitis as first symptoms. No genotype/phenotype correlation was observed in the remaining patients. CONCLUSIONS: Testing AIRE genotypes is useful to confirm an APECED diagnosis but also in investigating the pathogenesis and epidemiology of the disease in different regions.

A rare occurrence of non-classic congenital adrenal hyperplasia and type 1 diabetes mellitus in a girl with Prader-Willi Syndrome: Case report and review of the literature.

Prader-Willi syndrome (PWS) is a rare genetic disorder resulting from lack of expression of the paternally derived chromosome 15q11-13, associated with several complications, including pubertal disorders, short stature, hyperphagia, obesity, glucose metabolism abnormalities, scoliosis, obstructive sleep apnea syndrome (OSAS) and behavioral problems. We report the case of a girl affected by PWS who presented at the age of 5.9 with premature pubarche, accelerated linear growth and advanced bone age (BA). She was subsequently diagnosed with non-classic congenital adrenal hyperplasia (CAH) confirmed by genetic analysis. Considering the clinical, biochemical, and genetic findings, hydrocortisone therapy was started to prevent rapid BA acceleration and severe compromission of final height. During infancy, short stature and low levels of insulin-like growth factor-1 (IGF-1) for age and gender led to suspicion of growth hormone deficiency (GHD), confirmed by stimulation testing (arginine and clonidine). rhGH therapy was administered and continued until final height was reached. During endocrinological follow up she developed impaired glucose tolerance with positive markers of ß-cell autoimmunity (anti-glutamic acid decarboxylase antibodies, GAD Ab), which evolved over time into type 1 diabetes mellitus and insulin therapy with a basal-bolus scheme and an appropriate diet were needed.

Long-term effects of GH therapy in adult patients with Prader-Willi syndrome: a longitudinal study.

Introduction: Prader-Willi syndrome (PWS) is a complex disorder resulting from the failure of expression of paternal alleles in the PWS region of chromosome 15. The PWS phenotype resembles that observed in the classic non-PWS GH deficiency (GHD), including short stature, excessive fat mass, and reduced muscle mass. To date, a small number of studies on the long-term effects of GH treatment are available in adult subjects with PWS. Methods: In this longitudinal study, 12 obese subjects with PWS (GHD/non-GHD 6/6) were treated for a median of 17 years, with a median GH dose of 0.35 mg/day. The median age was 27.1 years. Anthropometric, body composition, hormonal, biochemical, and blood pressure variables were analyzed in all subjects. Results: Waist circumference was significantly lower at the end of the treatment period (p-value=0.0449), while body mass index (BMI) did not differ significantly. Compared to the baseline, a highly significant reduction of Fat Mass % (FM%) was observed (p-value=0.0005). IGF-I SDS values significantly increased during GH therapy (p-value=0.0005). A slight impairment of glucose homeostasis was observed after GH therapy, with an increase in the median fasting glucose levels, while insulin, HOMA-IR, and HbA1c values remained unchanged. Considering GH secretory status, both subjects with and without GHD showed a significant increase in IGF-I SDS and a reduction of FM% after GH therapy (p-value= 0.0313 for all). Discussion: Our results indicate that long-term GH treatment has beneficial effects on body composition and body fat distribution in adults with PWS associated with obesity. However, the increase in glucose values during GH therapy should be considered, and continuous surveillance of glucose metabolism is mandatory during long-term GH therapy, especially in subjects with obesity.

From Metabolic Syndrome to Type 2 Diabetes in Youth.

In the frame of metabolic syndrome, type 2 diabetes emerges along a continuum of the risk from the clustering of all its components, namely visceral obesity, high blood pressure and lipids, and impaired glucose homeostasis. Insulin resistance is the hallmark common to all the components and, in theory, is a reversible condition. Nevertheless, the load that this condition can exert on the ß-cell function at the pubertal transition is such as to determine its rapid and irreversible deterioration leading to plain diabetes. The aim of this review is to highlight, in the context of metabolic syndrome, age-specific risk factors that lead to type 2 diabetes onset in youth; resume age specific screening and diagnostic criteria; and anticipate potential for treatment. Visceral obesity and altered lipid metabolism are robust grounds for the development of the disease. Genetic differences in susceptibility to hampered ß-cell function in the setting of obesity and insulin resistance largely explain why some adolescents with obesity do develop diabetes at a young age and some others do not. Lifestyle intervention with a healthy diet and physical activity remains the pillar of the type 2 diabetes treatment in youth. As to the pharmacological management, metformin and insulin have failed to rescue ß-cell function and to ensure long-lasting glycemic control in youth. A new era might start with the approval for use in pediatric age of drugs largely prescribed in adults, such as dipeptidyl peptidase-4 and sodium-dependent glucose transport inhibitors, and of new weight-lowering drugs in the pipeline such as single and multiple agonists of the glucagon-like peptide 1 receptor. The latter drugs can have tremendous impact on the natural history of the disease. By treating diabetes, they will reduce the burden of all the metabolic abnormalities belonging to the syndrome while causing a tremendous weight loss hitherto never seen before.

Malignancies in Prader-Willi Syndrome: Results From a Large International Cohort and Literature Review.

CONTEXT: Prader-Willi syndrome (PWS) is a complex disorder combining hypothalamic dysfunction, neurodevelopmental delay, hypotonia, and hyperphagia with risk of obesity and its complications. PWS is caused by the loss of expression of the PWS critical region, a cluster of paternally expressed genes on chromosome 15q11.2-q13. As life expectancy of patients with PWS increases, age-related diseases like malignancies might pose a new threat to health. OBJECTIVE: To investigate the prevalence and risk factors of malignancies in patients with PWS and to provide clinical recommendations for cancer screening. METHODS: We included 706 patients with PWS (160 children, 546 adults). We retrospectively collected data from medical records on past or current malignancies, the type of malignancy, and risk factors for malignancy. Additionally, we searched the literature for information about the relationship between genes on chromosome 15q11.2-q13 and malignancies. RESULTS: Seven adults (age range, 18-55 years) had been diagnosed with a malignancy (acute lymphoblastic leukemia, intracranial hemangiopericytoma, melanoma, stomach adenocarcinoma, biliary cancer, parotid adenocarcinoma, and colon cancer). All patients with a malignancy had a paternal 15q11-13 deletion. The literature review showed that several genes on chromosome 15q11.2-q13 are related to malignancies. CONCLUSION: Malignancies are rare in patients with PWS. Therefore, screening for malignancies is only indicated when clinically relevant symptoms are present, such as unexplained weight loss, loss of appetite, symptoms suggestive of paraneoplastic syndrome, or localizing symptoms. Given the increased cancer risk associated with obesity, which is common in PWS, participation in national screening programs should be encouraged.

Kidney disease in adults with Prader-Willi syndrome: international cohort study and systematic literature review.

Background: Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria. Methods: We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS. Results: We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (p=0.027, p=0.019, p<0.001, p<0.001, p=0.011 and respectively). Conclusion: Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.

The Italian registry for patients with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients' care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. MATERIALS AND METHODS: The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. RESULTS: A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019-2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. CONCLUSIONS: The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

The treatment of obesity in children and adolescents: consensus position statement of the Italian society of pediatric endocrinology and diabetology, Italian Society of Pediatrics and Italian Society of Pediatric Surgery.

This Position Statement updates the different components of the therapy of obesity (lifestyle intervention, drugs, and surgery) in children and adolescents, previously reported in the consensus position statement on pediatric obesity of the Italian Society of Pediatric Endocrinology and Diabetology and the Italian Society of Pediatrics. Lifestyle intervention is the first step of treatment. In children older than 12 years, pharmacotherapy is the second step, and bariatric surgery is the third one, in selected cases. Novelties are available in the field of the medical treatment of obesity. In particular, new drugs demonstrated their efficacy and safety and have been approved in adolescents. Moreover, several randomized control trials with other drugs are in process and it is likely that some of them will become available in the future. The increase of the portfolio of treatment options for obesity in children and adolescents is promising for a more effective treatment of this disorder.

Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome.

OBJECTIVE: A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader-Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low-Dose Tetracosactrin Stimulation Test (LDTST), 1 µg] or standard-dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. DESIGN: Cross-sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. PATIENTS: Eighty-four children with PWS. MEASUREMENTS: Assessment of adrenal response by morning cortisol and ACTH dosage, and 1-µg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm; below this threshold, patients were submitted to a second test. Responses were correlated with the patients' clinical and molecular characteristics to assess genotype-phenotype correlation. RESULTS: Pathological cortisol peak responses to the LDTST were registered in 12 patients (14.3%) who had reduced basal (169.4 ± 83.3 nm) and stimulated (428.1 ± 69.6 nm) cortisol levels compared to patients with normal responses (367.1 ± 170.6 and 775.9 ± 191.3 nm, P < 0.001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0.001), and the patients' ages (P < 0.001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0.030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r(2) = 0.353, P < 0.001). Standard-dose (250 µg) tetracosactrin test confirmed CAI in 4/12 patients (4.8% of the cohort). CONCLUSIONS: Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.

Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation.

Gain-of-function mutations of KCNJ11 can cause permanent neonatal diabetes mellitus, but only rarely after 6 months of age. Specific uncommon mutations KCNJ11give rise to a syndrome defined as developmental delay, epilepsy, and neonatal diabetes (DEND), or - more frequently - to a milder sub-type lacking epilepsy, denoted as intermediate-DEND (iDEND). Our aim was to consider a possible monogenic etiology in a 12-yr-old boy with early onset diabetes and mild neurological features. We studied a subject diagnosed with diabetes at 21 months of age, and negative to type 1 diabetes autoantibodies testing. He had learning difficulties during primary school, and a single episode of seizures at the age of 10 yr. We performed direct DNA sequencing of the KCNJ11 gene with subsequent functional study of mutated channels in COSm6 cells. The patient's clinical response to oral glyburide (Glyb) was assessed. Motor coordination was evaluated before and after 6 and 12 months of Glyb therapy. Sequencing of the KCNJ11 gene detected the novel, spontaneous mutation S225T, combined with deletion of amino acids 226-232. In vitro studies revealed that the mutation results in a K(ATP) channel with reduced sensitivity to the inhibitory action of ATP. Glyb improved diabetes control (hemoglobin A1c on insulin: 52 mmol/mol/6.9%; on Glyb: 36 mmol/mol/5.4%) and also performance on motor coordination tests that were impaired before the switch of therapy. We conclude that KCNJ11/S225T, del226-232 mutation caused a mild iDEND form in our patient. KCNJ11 should be considered as the etiology of diabetes even beyond the neonatal period if present in combination with negative autoantibody testing and even mild neurological symptoms.