Lessons from prospective longitudinal follow-up of a French APECED cohort.

BACKGROUND: APECED syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad "hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC)" and non-endocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations and to characterize immunological disturbances in a French cohort. PATIENTS AND METHODS: A national, multicenter prospective observational study to collect genetic, clinical, biological and immunological data (NCT03751683). RESULTS: 25 patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, two of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. 17/25 patients were homozygote. The median number of clinical manifestations was seven; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had NK cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (p < 0.001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-interleukin-22 antibodies, and 13/18 for anti-interleukin-17F antibodies, without clear phenotypic correlation other than with CMC. CONCLUSION: This first prospective cohort showed a high AIRE genotype variability, with two new gene variants. The prevalence of potentially life-threatening non-endocrine manifestations, was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination, and targeted therapeutic approaches.

Compound genetic etiology in a patient with a syndrome including diabetes, intellectual deficiency and distichiasis.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Characteristics of newly diagnosed type 1 diabetes in paediatric and adult population from Reims University Hospital, France from 1997 to 2019.

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.

International comparison of glycaemic control in people with type 1 diabetes: an update and extension.

AIMS: To update and extend a previous cross-sectional international comparison of glycaemic control in people with type 1 diabetes. METHODS: Data were obtained for 520,392 children and adults with type 1 diabetes from 17 population and five clinic-based data sources in countries or regions between 2016 and 2020. Median HbA1c (IQR) and proportions of individuals with HbA1c < 58 mmol/mol (<7.5%), 58-74 mmol/mol (7.5-8.9%) and ≥75 mmol/mol (≥9.0%) were compared between populations for individuals aged <15, 15-24 and ≥25 years. Logistic regression was used to estimate the odds ratio (OR) of HbA1c < 58 mmol/mol (<7.5%) relative to ≥58 mmol/mol (≥7.5%), stratified and adjusted for sex, age and data source. Where possible, changes in the proportion of individuals in each HbA1c category compared to previous estimates were calculated. RESULTS: Median HbA1c varied from 55 to 79 mmol/mol (7.2 to 9.4%) across data sources and age groups so a pooled estimate was deemed inappropriate. OR (95% CI) for HbA1c < 58 mmol/mol (<7.5%) were 0.91 (0.90-0.92) for women compared to men, 1.68 (1.65-1.71) for people aged <15 years and 0.81 (0.79-0.82) aged15-24 years compared to those aged ≥25 years. Differences between populations persisted after adjusting for sex, age and data source. In general, compared to our previous analysis, the proportion of people with an HbA1c  < 58 mmol/l (<7.5%) increased and proportions of people with HbA1c ≥ 75 mmol/mol (≥9.0%) decreased. CONCLUSIONS: Glycaemic control of type 1 diabetes continues to vary substantially between age groups and data sources. While some improvement over time has been observed, glycaemic control remains sub-optimal for most people with Type 1 diabetes.

A large extended family with hyperparathyroidism-jaw tumor syndrome due to deletion of the third exon of CDC73: clinical and molecular features.

PURPOSE: We described the phenotype of a large 4-generation family with Hyperparathyrodism-Jaw Tumor syndrome (HPT-JT) associated with a rare deletion of exon 3 of the CDC73 gene. METHODS: We collected medical, genetic data on 24 family members descended from a common ancestor carrying a heterozygous deletion of exon 3. RESULTS: Thirteen carried the deletion, the penetrance was estimated at 50% at 40 years. Seven patients (39 ± 14.5 years) presented with HPT which could start at 13. Median plasmatic calcium and PTH levels were 3.13 ± 0.7 mmol/L and 115 ± 406 pg/ml, respectively. Kidney disease related to hypercalcemia were present in 57.1% of patients. All seven patients underwent surgery to remove a single parathyroid adenoma. One recurrence occurred 7 years post-surgery. No parathyroid carcinoma has been found to date. We found two atypical parathyroid adenomas. We described an additional somatic variant in exon 1 of gene CDC73 in two tumors. Jaw tumors were not necessarily associated with hyperparathyroidism, as shown in one case. Two kidney cysts were also reported. Variable phenotype expressivity was emphasized by clinical presentations in 2 monozygotic twins: acute hypercalcemia, kidney failure and ossifying fibroma in one twin, versus normocalcemic parathyroid adenoma in the other one. CONCLUSION: We report a family carrier of a deletion of exon 3 of the CDC73 gene. This is characterized by a high level of hypercalcemia, deleterious kidney effects and atypical parathyroid adenomas without carcinomas. Onset and intensity of HPT remain unpredictable. The additional somatic mutation found in the parathyroid tumor could lead to these phenotypical variations.

Increasing knowledge in IGF1R defects: lessons from 35 new patients.

BACKGROUND: 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 IGF1R defect was described, from which a clinical score was established for diagnosis. We assessed this score in a large cohort of patients with identified IGF1R 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. METHODS: 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. RESULTS: We detected 21 IGF1R 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 IGF1R. Functional studies showed that the SNVs tested were associated with decreased AKT phosphorylation. CONCLUSION: We report eight new pathogenic variants of IGF1R and an original case with a homozygous SNV. We found the recently proposed clinical score to be accurate for the diagnosis of IGF1R 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.

Three Consecutive Pregnancies in a Patient with Chronic Autoimmune Thyroid Disease Associated with Hypothyroidism and Extremely High Levels of Anti-Thyrotropin Receptor Antibodies.

Background: Thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal thyroid dysfunction and serious complications. Patient Findings: We report the case of a woman with autoimmune hypothyroidism and extremely high TRAb levels, with blocking and stimulating activities (biological activities characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first pregnancy, sonography detected fetal growth retardation and cardiac abnormalities (extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother's TRAb level, assayed later, was 4030 IU/L (n < 10). Delivered via caesarean section gestational week 30, the newborn girl had several malformations, signs of malnutrition, goiter and hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days after delivery. Faced with persistently high TRAb levels and a desire to become pregnant again, the woman was treated with three consecutive 740-MBq activities of iodine-131, which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent pregnancies 16 and 72 months after the radioiodine administration. During the close follow-ups, fetal development was normal, and initial TRAb levels during the two pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns, mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively. The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in good health. The mother has no detectable thyroid gland tissue and is euthyroid on levothyroxine (175 µg/d). Her TRAb level gradually decreased to 136 IU/L. Summary and Conclusions: This remarkable case illustrates the severe consequences of untreated fetal hyperthyroidism and the need to assay and follow-up TRAb levels in women of reproductive age with autoimmune thyroiditis.

Early predictors of diabetic retinopathy in type 1 diabetes: The Retinopathy Champagne Ardenne Diabète (ReCAD) study.

AIMS: To determine the relationship between early markers of diabetes control and diabetic retinopathy (DR) in type 1 diabetes. METHODS: 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. RESULTS: 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). CONCLUSION: 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.

NNT mutations: a cause of primary adrenal insufficiency, oxidative stress and extra-adrenal defects.

OBJECTIVE: Nicotinamide nucleotide transhydrogenase (NNT), one of the several genes recently discovered in familial glucocorticoid deficiencies (FGD), is involved in reactive oxygen species detoxification, suggesting that extra-adrenal manifestations may occur, due to the sensitivity to oxidative stress of other organs rich in mitochondria. Here, we sought to identify NNT mutations in a large cohort of patients with primary congenital adrenal insufficiency without molecular etiology and evaluate the degree of adrenal insufficiency and onset of extra-adrenal damages. METHODS: Sanger or massive parallel sequencing of NNT and patient monitoring. RESULTS: Homozygous or compound heterozygous NNT mutations occurred frequently (26%, 13 unrelated families, 18 patients) in our cohort. Seven new mutations were identified: p.Met337Val, p.Ala863Glu, c.3G>A (p.Met1?), p.Arg129*, p.Arg379*, p.Val665Profs*29 and p.Ala704Serfs*19. The most frequent mutation, p.Arg129*, was found recurrently in patients from Algeria. Most patients were diagnosed belatedly (8-18 months) after presenting severe hypoglycemia; others experiencing stress conditions were diagnosed earlier. Five patients also had mineralocorticoid deficiency at onset. One patient had congenital hypothyroidism and two cryptorchidism. In follow-up, we noticed gonadotropic and genitalia impairments (precocious puberty, testicular inclusions, interstitial Leydig cell adenoma, azoospermia), hypothyroidism and hypertrophic cardiomyopathy. Intrafamilial phenotype heterogeneity was also observed. CONCLUSIONS: NNT should be sequenced, not only in FGD, but also in all primary adrenal insufficiencies for which the most frequent etiologies have been ruled out. As NNT is involved in oxidative stress, careful follow-up is needed to evaluate mineralocorticoid biosynthesis extent, and gonadal, heart and thyroid function.

Early Formation of Serum Advanced Glycation End-Products in Children with Type 1 Diabetes Mellitus: Relationship with Glycemic Control.

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.

A pure familial 6q15q21 split duplication associated with obesity and transmitted with partial reduction.

Familial transmission of chromosome 6 duplications is rare. We report on the first observation of a maternally-inherited pure segmental 6q duplication split into two segments, 6q15q16.3 and 6q16.3q21, and associated with obesity. Obesity has previously been correlated to chromosome 6 q-arm deletion but has not yet been assessed in duplications. The aim of this study was to characterize the structure of these intrachromosomal insertional translocations by classic cytogenetic banding, array-CGH, FISH, M-banding and genotyping using microsatellites and SNP array analysis, in a mother and four offspring. The duplicated 6q segments, 9.75 Mb (dup 1) and 7.05 Mb (dup 2) in size in the mother, were inserted distally into two distinct chromosome 6q regions. They were transmitted to four offspring. A son and a daughter inherited the two unbalanced insertions and displayed, like the mother, an abnormal phenotype with facial dysmorphism, intellectual disability, and morbid obesity. Curiously, two daughters with a normal phenotype inherited only the smaller segment, 6q16.3q21. The abnormal phenotype was associated with the larger proximal 6q15q16.3 duplication. We hypothesize a mechanism for this exceptional phenomenon of recurrent reduction and transmission of the duplication during meiosis in a family. We expect the interpretation of our findings to be useful for genetic counseling and for understanding the mechanisms underlying these large segmental 6q duplications and their evolution.

Macroprolactinomas in children and adolescents: factors associated with the response to treatment in 77 patients.

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.

Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Neuropsychological dysfunction and developmental defects associated with genetic changes in infants with neonatal diabetes mellitus: a prospective cohort study [corrected].

BACKGROUND: Neonatal diabetes mellitus is a rare genetic form of pancreatic ß-cell dysfunction. We compared phenotypic features and clinical outcomes according to genetic subtypes in a cohort of patients diagnosed with neonatal diabetes mellitus before age 1 year, without ß-cell autoimmunity and with normal pancreas morphology. METHODS: We prospectively investigated patients from 20 countries referred to the French Neonatal Diabetes Mellitus Study Group from 1995 to 2010. Patients with hyperglycaemia requiring treatment with insulin before age 1 year were eligible, provided that they had normal pancreatic morphology as assessed by ultrasonography and negative tests for ß-cell autoimmunity. We assessed changes in the 6q24 locus, KATP-channel subunit genes (ABCC8 and KCNJ11), and preproinsulin gene (INS) and investigated associations between genotype and phenotype, with special attention to extra-pancreatic abnormalities. FINDINGS: We tested 174 index patients, of whom 47 (27%) had no detectable genetic defect. Of the remaining 127 index patients, 40 (31%) had 6q24 abnormalities, 43 (34%) had mutations in KCNJ11, 31 (24%) had mutations in ABCC8, and 13 (10%) had mutations in INS. We reported developmental delay with or without epilepsy in 13 index patients (18% of participants with mutations in genes encoding KATP channel subunits). In-depth neuropsychomotor investigations were done at median age 7 years (IQR 1-15) in 27 index patients with mutations in KATP channel subunit genes who did not have developmental delay or epilepsy. Developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits were recorded in all index patients who had this testing. Compared with index patients who had mutations in KATP channel subunit genes, those with 6q24 abnormalities had specific features: developmental defects involving the heart, kidneys, or urinary tract (8/36 [22%] vs 2/71 [3%]; p=0·002), intrauterine growth restriction (34/37 [92%] vs 34/70 [48%]; p<0·0001), and early diagnosis (median age 5·0 days, IQR 1·0-14·5 vs 45·5 days, IQR 27·2-95·0; p<0·0001). Remission of neonatal diabetes mellitus occurred in 89 (51%) index patients at a median age of 17 weeks (IQR 9·5-39·0; median follow-up 4·7 years, IQR 1·5-12·8). Recurrence was common, with no difference between the groups who had 6q24 abnormalities versus mutations in KATP channel subunit genes (82% vs 86%; p=0·36). INTERPRETATION: Neonatal diabetes mellitus is often associated with neuropsychological dysfunction and developmental defects that are specific to the underlying genetic abnormality. A multidisciplinary assessment is therefore essential when patients are diagnosed. Features of neuropsychological dysfunction and developmental defects should be tested for in adults with a history of neonatal diabetes mellitus. FUNDING: Agence Nationale de la Recherche-Maladies Rares Research Program Grant, the Transnational European Research Grant on Rare Diseases, the Société Francophone du Diabète-Association Française du Diabète, the Association Française du Diabète, Aide aux Jeunes Diabétiques, a CIFRE grant from the French Government, HRA-Pharma, the French Ministry of Education and Research, and the Société Française de Pédiatrie.

Deficit in anterior pituitary function and variable immune deficiency (DAVID) in children presenting with adrenocorticotropin deficiency and severe infections.

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.

Metabolic control in children with diabetes mellitus who are younger than 6 years at diagnosis: continuous subcutaneous insulin infusion as a first line treatment?

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.

An unusual case of methyl bromide poisoning.

A nonlethal poisoning case by methyl bromide in a young woman due to leakage of old fire extinguishers is described. The patient developed major action and intention myoclonus the day following exposure. Inorganic bromide concentrations in plasma were determined by inductively coupled plasma mass spectrometry. The initial plasma bromide level was 202 mg/L, 40-fold in excess than the commonly accepted tolerance limit, and decreased slowly to normal levels within 2 months. Although plasma inorganic bromide concentration is known not to be directly correlated to the severity of organic bromide poisoning, its determination was, in the present case, particularly useful to confirm the diagnosis. One year post-exposure, the patient showed no sign of central nervous system toxicity. While such a case of poisoning is particularly rare today, it illustrates, however, that the danger still exists in France although the destruction