Objectives To quantify serum advanced glycation end-products (AGEs) at the onset of type 1 diabetes mellitus and to determine their potential usefulness as retrospective indicators of glycemic ...balance. Study design Carboxymethyllysine (CML) and pentosidine concentrations were determined by liquid chromatography–tandem mass spectrometry in 3 groups of children with type 1 diabetes mellitus: group (Gr) 1, subjects included at disease onset (n = 36); Gr2, subjects with diabetes of 5 years duration (n = 48); Gr3, subjects with diabetes of 10 years duration and in control subjects (n = 33). Hemoglobin A1c (HbA1c) values were recorded over the entire course of treatment for assessing long-term glycemic balance. Results Serum AGE concentrations were increased in all groups of subjects with diabetes compared with control subjects, but were highest in Gr1 (for CML: 0.155, 0.306, 0.219, and 0.224 mmol/mol Lys in control, Gr1, Gr2, and Gr3 subjects, respectively; for pentosidine: 312, 492, 365, and 403 nmol/mol Lys, respectively). AGE concentrations were closely correlated with HbA1c values ( r = 0.78 for CML; r = 0.49 for pentosidine). In Gr2 and Gr3, the overall glycemic balance estimated by average HbA1c values was positively correlated with CML and pentosidine concentrations, especially in the first year of follow-up. Conclusion Our results indicate that AGE concentrations are elevated in serum at the time of diabetes mellitus diagnosis, suggesting that the deleterious role of AGEs in the development of long-term complications should be taken into account even at the initial stages of the disease. Moreover, in some circumstances, AGEs could serve as surrogate markers of HbA1c for monitoring glycemic control.
To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes.
A historic cohort study was conducted on 712 patients from the CARéDIAB ...database. HbA1c and usual metabolic parameters were measured one year after diagnosis of diabetes. First occurrences of severe hypoglycemia and ketoacidosis during follow-up were selected as time-dependent markers of diabetes control. Data were analyzed in a Cox model using SPSS software to predict DR with significance level at p-value <0.05.
In multivariate regression, any diabetic retinopathy was predicted by HbA1c (HR = 1.38; CI = 1.25–1.52; p < 0.0001), severe hypoglycemia (HR = 3; CI = 1.99–4.52; p < 0.0001), ketoacidosis (HR = 1.96; CI = 1.17–3.22; p = 0.009), and age at diagnosis (HR = 1.016; CI = 1.002–1.031; p = 0.02). Proliferative DR was predicted by HbA1c (HR = 1.67; CI = 1.51–1.79; p < 0.0001), severe hypoglycemia (HR = 3.67; CI = 2.74–5.25; p < 0.0001), and ketoacidosis (HR = 2.37; CI = 1.56–3.18; p < 0.0001).
This study shows that the failure to achieve diabetes control after the first year of diagnosis as well as early episodes of acute diabetes complications may contribute to the occurrence of diabetic retinopathy in type 1 diabetes patients.
The type 1 insulin-like growth factor receptor (IGF1R) is a keystone of fetal growth regulation by mediating the effects of IGF-I and IGF-II. Recently, a cohort of patients carrying an
defect was ...described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified
defects, as no external validation was available. Furthermore, we aimed to develop a functional test to allow the classification of variants of unknown significance (VUS) in vitro.
DNA was tested for either deletions or single nucleotide variant (SNV) and the phosphorylation of downstream pathways studied after stimulation with IGF-I by western blot analysis of fibroblast of nine patients.
We detected 21
defects in 35 patients, including 8 deletions and 10 heterozygous, 1 homozygous and 1 compound-heterozygous SNVs. The main clinical characteristics of these patients were being born small for gestational age (90.9%), short stature (88.2%) and microcephaly (74.1%). Feeding difficulties and varying degrees of developmental delay were highly prevalent (54.5%). There were no differences in phenotypes between patients with deletions and SNVs of
. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation.
We report eight new pathogenic variants of
and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of
defects with a sensitivity of 95.2%. We developed an efficient functional test to assess the pathogenicity of SNVs, which is useful, especially for VUS.
Background:
Pituitary adenomas are rare in children and adolescents. The response of macroprolactinomas to dopamine agonists (DA) in this age group has been less extensively studied than in adults.
...Objective:
We retrospectively analyzed data on a large cohort of young patients with macroprolactinomas.
Patients and Methods:
Patients aged younger than 20 years at macroprolactinoma diagnosis and seen in three tertiary referral centers between 1983 and 2013 were studied by analyzing their clinical and genetic (AIP and MEN1) characteristics. Hormonal and tumoral responses to DA were analyzed, and the patients' status at their last visit, after a mean (±SD) follow-up of 8.2 ± 5.8 years, was assessed.
Results:
The cohort comprised 77 patients (26 males, 51 females). Mean age at diagnosis was 16.1 ± 2.5 years (range, 4.5–20 y). In both sexes, the most frequent revealing symptom was a pubertal disorder (49%), followed by visual problems (24%) and growth retardation (24%). Basal prolactin (PRL) levels and maximal tumor diameter were significantly higher in boys than in girls (7168 ng/mL, 202–40 168 vs 1433 ng/mL, 115–20 000, P = .002; and 33 ± 14 mm, 15–64 vs 19 ± 9 mm; 10–50, P < .001, respectively). PRL levels normalized in 74% of the patients treated with DA. A mutation of AIP or MEN1 was found in 14% of the patients. Factors associated with resistance to DA were young age, higher PRL levels, larger volume, and the presence of a MEN1 (but not an AIP) mutation.
Conclusion:
Macroprolactinomas are rare below the age of 20 years, mainly occurring in girls and during adolescence. Like adults, young patients are very sensitive to DA, which should therefore be considered the first-line treatment. DA resistance is associated with a higher PRL level and larger tumor size, both parameters being closely linked together. About 14% of these young patients have an AIP or MEN1 mutation, this latter being an independent predictor of DA resistance.
DAVID syndrome is a rare condition combining anterior pituitary hormone deficiency with common variable immunodeficiency. NFKB2 mutations have recently been identified in patients with ACTH and ...variable immunodeficiency. A similar mutation was previously found in Nfkb2 in the immunodeficient Lym1 mouse strain, but the effect of the mutation on endocrine function was not evaluated.
We ascertained six unrelated DAVID syndrome families. We performed whole exome and traditional Sanger sequencing to search for causal genes. Lym1 mice were examined for endocrine developmental anomalies.
Mutations in the NFKB2 gene were identified in three of our families through whole exome sequencing, and in a fourth by direct Sanger sequencing. De novo origin of the mutations could be demonstrated in three of the families. All mutations lie near the C-terminus of the protein-coding region, near signals required for processing of NFΚB2 protein by the alternative pathway. Two of the probands had anatomical pituitary anomalies, and one had growth and thyroid hormone as well as ACTH deficiency; these findings have not been previously reported. Two children of one of the probands carried the mutation and have to date exhibited only an immune phenotype. No mutations were found near the C-terminus of NFKB2 in the remaining two probands; whole exome sequencing has been performed for one of these. Lym1 mice, carrying a similar Nfkb2 C-terminal mutation, showed normal pituitary anatomy and expression of proopiomelanocortin (POMC).
We confirm previous findings that mutations near the C-terminus of NFKB2 cause combined endocrine and immunodeficiencies. De novo status of the mutations was confirmed in all cases for which both parents were available. The mutations are consistent with a dominant gain-of-function effect, generating an unprocessed NFKB2 super-repressor protein. We expand the potential phenotype of such NFKB2 mutations to include additional pituitary hormone deficiencies as well as anatomical pituitary anomalies. The lack of an observable endocrine phenotype in Lym1 mice suggests that the endocrine component of DAVID syndrome is either not due to a direct role of NFKB pathways on pituitary development, or else that human and mouse pituitary development differ in its requirements for NFKB pathway function.
We studied a young woman with atypical diabetes associated with mild intellectual disability, lymphedema distichiasis syndrome (LDS) and polymalformative syndrome including distichiasis. We used ...different genetic tools to identify causative pathogenic mutations and/or copy number variations.
Although proband's, diabetes mellitus occurred during childhood, type 1 diabetes was unlikely due to the absence of detectable autoimmunity. DNA microarray analysis first identified a de novo, heterozygous deletion at the chr16q24.2 locus. Previously, thirty-three pathogenic or likely pathogenic deletions encompassing this locus have been reported in patients presenting with intellectual deficiency, obesity and/or lymphedema but not with diabetes. Of note, the deletion encompassed two topological association domains, whose one included FOXC2 that is known to be linked with LDS. Via whole-exome sequencing, we found a heterozygous, likely pathogenic variant in WFS1 (encoding wolframin endoplasmic reticulum ER transmembrane glycoprotein) which was inherited from her father who also had diabetes. WFS1 is known to be involved in monogenic diabetes. We also found a likely pathogenic variant in USP9X (encoding ubiquitin specific peptidase 9 X-linked) that is involved in X-linked intellectual disability, which was inherited from her mother who had dyscalculia and dyspraxia.
Our comprehensive genetic analysis suggested that the peculiar phenotypes of our patient were possibly due to the combination of multiple genetic causes including chr16q24.2 deletion, and two likely pathogenic variants in WFS1 and USP9X.
French health insurance data showed that the incidence of type 1 diabetes mellitus (T1DM) in children increased over the years to 2015. The objective of our study was to assess the evolution of the ...number of incident cases of paediatric and adult type 1 diabetes in our institution, and to describe their clinical presentation and its evolution. All patients with T1DM managed at diagnosis at Reims University Hospital between 1997 and 2019 were included. The clinical and biological data were extracted from the Champagne-Ardenne Diabetes Network database. Included were 847 patients with a median age of 10.3 years. Diagnosis was established in 71% of cases before 15 years, 7.4% after 35 years. The number of newly diagnosed cases was 3.6-times higher in 2019 compared to 1997. Ketoacidosis, the frequency of which decreased with age (P < 0.0001), revealed diabetes in a total of 32% of cases and in 46% of children under 5 years. It was more severe in children than in adults (P = 0.03), and its frequency increased over the study period. Hypotrophy was found in 23% of children under 15 years of age, and was more pronounced before 5 years of age, with no improvement over time. We saw an increase in the frequency of obesity or overweight among adults. Our study showed an increase in incident cases of diabetes in our hospital that continued over time for both children and adults. Clinical features at diagnosis deteriorated during this period for those under 15 years of age with an increase in ketoacidosis frequency.
Objective To assess long-term metabolic outcomes in children with diabetes mellitus that was diagnosed when they were <6 years old. Study design A cohort of 66 children with diabetes mellitus that ...had a duration of at least 5 years and was diagnosed before they were 6 years old. Thirty-four children were treated at diagnosis with multiple daily subcutaneous insulin injections (MDI), and all these children, except 3, were switched to continuous subcutaneous insulin infusion (CSII; group A). Thirty-two children received CSII as initial treatment (group B). Results Hemoglobin A1c values were significantly lower in patients receiving CSII than MDI during all the 8 years of follow-up except one (year 1: 6.9% ± 0.9% versus 7.6% ± 1%, P = .011 ; year 4: 7.4% ± 0.8% versus 8.1% ± 0.9%, P = .006; year 7: 7.6% ± 0.5% versus 8.3% ± 0.8%, P = .001). The incidence of severe hypoglycemia was greatly decreased for the CSII group (9.8 versus 22.3 episodes/100 patient-years, P = .016). In group A, hemoglobin A1c values increased during the study period, and in group B, they increased only during the first 2 years and remained constant thereafter. Only 9.1% of patients did not use or abandoned CSII. Conclusion CSII in children <6 years of age enables better long-term metabolic control and lowers the risk of severe hypoglycemia better than MDI, especially when initiated at diagnosis.
Context:
Among 22 independent patients from the GENHYPOPIT network who had ACTH deficiency and no identified mutation of TPIT, three of them (13.6%) displayed common variable immunodeficiency (CVID), ...characterized by defective Ig production.
Objective:
Our objective was to describe an as yet unrecognized disease association.
Design:
We considered the hypothesis of ACTH deficiency being associated with antipituitary autoimmunity or lymphocytic hypophysitis. In the context of a functional network between the immune and endocrine systems, we also tested the hypothesis of a common genetic cause using a candidate gene approach.
Setting:
This was a multicentric study in three academic hospitals.
Patients:
We report four patients from three unrelated families presenting with ACTH deficiency and CVID.
Main Outcome Measures:
Detection of antipituitary autoantibodies, and sequencing of candidate genes (LIF, IKAROS, EOS) were the main outcome measures.
Results:
All patients including a pedigree with two affected siblings had ACTH deficit diagnosed from 5–15 yr, with symptomatic hypoglycemia, and CVID diagnosed from 2–8 yr revealed by recurrent infections. Three of the four patients had a hypoplastic pituitary. One patient had low IGF-I and subnormal GH response to stimulation, suggesting that secretion of other pituitary hormones may also be affected. All patients proved negative for pituitary autoantibodies and had no alteration in any of the genes tested.
Conclusions:
The remarkable association of two rare disorders affecting two functionally related systems in four patients from three independent pedigrees including a familial case provides strong evidence of the existence of a disease association: deficit in anterior pituitary function and variable immune deficiency, or DAVID.
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