Genetics and Natural History of Non-pancreatectomized Patients With Congenital Hyperinsulinism Due to Variants in ABCC8.

CONTEXT: Patients with congenital hyperinsulinism due to ABCC8 variants generally present severe hypoglycemia and those who do not respond to medical treatment typically undergo pancreatectomy. Few data exist on the natural history of non-pancreatectomized patients. OBJECTIVE: This work aims to describe the genetic characteristics and natural history in a cohort of non-pancreatectomized patients with congenital hyperinsulinism due to variants in the ABCC8 gene. METHODS: Ambispective study of patients with congenital hyperinsulinism with pathogenic or likely pathogenic variants in ABCC8 treated in the last 48 years and who were not pancreatectomized. Continuous glucose monitoring (CGM) has been periodically performed in all patients since 2003. An oral glucose tolerance test was performed if hyperglycemia was detected in the CGM. RESULTS: Eighteen non-pancreatectomized patients with ABCC8 variants were included. Seven (38.9%) patients were heterozygous, 8 (44.4%) compound heterozygous, 2 (11.1%) homozygous, and 1 patient carried 2 variants with incomplete familial segregation studies. Seventeen patients were followed up and 12 (70.6%) of them evolved to spontaneous resolution (median age 6.0 ± 4 years; range, 1-14). Five of these 12 patients (41.7%) subsequently progressed to diabetes with insufficient insulin secretion. Evolution to diabetes was more frequent in patients with biallelic variants in the ABCC8 gene. CONCLUSION: The high remission rate observed in our cohort makes conservative medical treatment a reliable strategy for the management of patients with congenital hyperinsulinism due to ABCC8 variants. In addition, a periodic follow-up of glucose metabolism after remission is recommended, as a significant proportion of patients evolved to impaired glucose tolerance or diabetes (biphasic phenotype).

Achievement of metabolic control among children and adolescents with type 1 diabetes in Spain.

AIMS: To assess metabolic control in a paediatric T1D population in Spain and analyse the rate of severe acute decompensations and chronic complications. METHODS: Data from patients treated at eight paediatric diabetes units with experienced diabetes teams between June and December 2014 were analysed in an observational prospective study. Variables included: age, sex, diabetes duration, number of follow-up visits/year, anthropometrical data, insulin treatment modalities, mean annual HbA1c and the prevalence of acute and chronic complications. SPSS statistics 21.0 was used. RESULTS: A total of 853 patients (49.7% female) with a mean age of 12.1 ± 3.7 years were included. Anthropometric data were normal. Mean diabetes duration was 8 ± 3.4 years. Mean outpatient follow-up was 4.7 ± 0.04 visits/year. Twenty-five per cent were on continuous subcutaneous insulin infusion (CSII). Mean HbA1c was 7.3 ± 1% (56 ± 8 mmol/mol) and 66.6% had HbA1c < 7.5% (58 mmol/mol). HbA1c value correlated negatively with age at onset and positively with years of diabetes, number of visits/year and current age (F = 7.06; p = 0.01). Patients on CSII (n = 213) were younger, attended the outpatient clinic more frequently, were diagnosed earlier, had better metabolic control and had presented more severe hypoglycaemic episodes the previous year. The rate of severe decompensation (episodes/100 patients/year) was ketoacidosis 1.5 and severe hypoglycaemia 4.5. The prevalence of chronic complications was very low. CONCLUSIONS: Our data describe the good compliance of paediatric T1D patients treated at eight paediatric units in Spain following international standards of metabolic control.

Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis.

CONTEXT: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

Structural pituitary abnormalities associated with CHARGE syndrome.

INTRODUCTION: CHARGE syndrome is a multisystem disorder that, in addition to Kallmann syndrome/isolated hypogonadotrophic hypogonadism, has been associated with anterior pituitary hypoplasia (APH). However, structural abnormalities such as an ectopic posterior pituitary (EPP) have not yet been described in such patients. OBJECTIVE: The aims of the study were: 1) to describe the association between CHARGE syndrome and a structurally abnormal pituitary gland; and 2) to investigate whether CHD7 variants, which are identified in 65% of CHARGE patients, are common in septo-optic dysplasia /hypopituitarism. METHODS: We describe 2 patients with features of CHARGE and EPP. CHD7 was sequenced in these and other patients with septo-optic dysplasia/hypopituitarism. RESULTS: EPP, APH, and GH, TSH, and probable LH/FSH deficiency were present in 1 patient, and EPP and APH with GH, TSH, LH/FSH, and ACTH deficiency were present in another patient, both of whom had features of CHARGE syndrome. Both had variations in CHD7 that were novel and undetected in control cohorts or in the international database of CHARGE patients, but were also present in their unaffected mothers. No CHD7 variants were detected in the patients with septo-optic dysplasia/hypopituitarism without additional CHARGE features. CONCLUSION: We report a novel association between CHARGE syndrome and structural abnormalities of the pituitary gland in 2 patients with variations in CHD7 that are of unknown significance. However, CHD7 mutations are an uncommon cause of septo-optic dysplasia or hypopituitarism. Our data suggest the need for evaluation of pituitary function/anatomy in patients with CHARGE syndrome.

Diagnostic value of the skin lesions in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

We report a child with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome due to a de novo c.1190G>A (p.R397Q) mutation in exon 11 of the forkhead domain of the FOXP3 gene. He had chronic dermatitis with an eczematous and ichthyosiform appearance and had an allogeneic bone marrow transplantation. IPEX syndrome is a rare, often fatal recessive disease caused by mutations in the FOXP3 gene on the X chromosome (Xp11.23-q13.3).

ACTYBOSS: activity, behavioral therapy in young subjects--after-school intervention pilot project on obesity prevention.

AIMS: To test the feasibility of a school-based intervention, which combines an incentive-driven physical activity program with lifestyle lectures, and its potential beneficial outcome on children's metabolic parameters. METHODS: We conducted a 6-month pilot intervention in two high schools in Mallorca, Spain, consisting of a program which involved free supervised exercise sessions and nutritional lectures, where children received credit points as a reward for the hours spent exercising and attendance to the lectures. The credit-earned points obtained were exchanged for gifts. We developed personalized cards and a web application for the participants to check the gifts they were eligible for (www.actyboss.com). Percentage body fat, percentage of fat-free mass and BMI were measured. Secondary measures included fitness parameters, blood pressure and blood lipids levels. 90 children signed up the consent form and 56 completed the program until the endpoint. RESULTS: We found a beneficial effect on body composition, fitness parameters, and systolic blood pressure in children who participated in ACTYBOSS compared to children who did not start the intervention. CONCLUSIONS: We describe the incentive-driven, after-school intervention pilot program to promote physical activity and a healthy lifestyle. The program had a positive effect on anthropometric measurements. A larger incentive-driven healthy lifestyle program is now ongoing.

Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia.

CONTEXT: Up to 90% of circulating IGF-I and IGF-II are carried bound to either IGF binding protein (IGFBP)-3 or IGFBP-5 and the acid-labile subunit (ALS) in the form of tertiary complexes that extend their circulating half-life. Three cases of complete ALS deficiency have been recently reported in short-stature patients with very low circulating IGF-I and IGFBP-3 levels who presented with homozygous or compound heterozygous mutations in the ALS encoding gene (IGFALS; 16p13.3), thus supporting a role for ALS in the regulation of the bioavailability of IGFs during postnatal growth. OBJECTIVE: We present the molecular and clinical characterization of two novel IGFALS mutations that caused complete ALS deficiency in three unrelated patients with postnatal growth deficit, low IGF-I and IGFBP-3 levels, and no GH deficiency. RESULTS: IGFALS mutation screening identified a novel homozygous IGFALS missense mutation, which altered a conserved residue, N276S, in two of the probands. The third proband presented a novel homozygous nonsense mutation, Q320X, that is predicted to generate a severely truncated ALS protein. The affected probands presented a similar phenotype characterized by a moderate postnatal growth deficit associated with undetectable ALS, low IGF-I, IGF-II, and IGFBP-3, and hyperinsulinemia, and, in two cases, delayed puberty. CONCLUSIONS: Primary ALS deficiency due to IGFALS mutations should be considered as a possible cause of postnatal growth deficit in IGF-I-deficient patients in the absence of GH deficiency or insensitivity. Determination of serum ALS levels and basal insulinemia can be helpful in the differential diagnosis of patients with idiopathic IGF-I deficiency.