Isabelle Flechtner

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

BACKGROUND Neonatal diabetes mellitus is a rare genetic form of pancreatic β-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 β-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 β-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.

Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

OBJECTIVE Neonatal diabetes secondary to mutations in potassium-channel subunits is a rare disease but constitutes a paradigm for personalized genetics-based medicine, as replacing the historical treatment with insulin injections with oral sulfonylurea (SU) therapy has been proven beneficial. SU receptors are widely expressed in the brain, and we therefore evaluated potential effects of SU on neurodevelopmental parameters, which are known to be unresponsive to insulin. RESEARCH DESIGN AND METHODS We conducted a prospective single-center study. Nineteen patients (15 boys aged 0.1–18.5 years) were switched from insulin to SU therapy. MRI was performed at baseline. Before and 6 or 12 months after the switch, patients underwent quantitative neurological and developmental assessments and electrophysiological nerve and muscle testing. RESULTS At baseline, hypotonia, deficiencies in gesture conception or realization, and attention disorders were common. SU improved HbA1c levels (median change −1.55% [range −3.8 to 0.1]; P < 0.0001), intelligence scores, hypotonia (in 12 of 15 patients), visual attention deficits (in 10 of 13 patients), gross and fine motor skills (in all patients younger than 4 years old), and gesture conception and realization (in 5 of 8 older patients). Electrophysiological muscle and nerve tests were normal. Cerebral MRI at baseline showed lesions in 12 patients, suggesting that the impairments were central in origin. CONCLUSIONS SU therapy in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients. An early genetic diagnosis should always be made, allowing for a rapid switch to SU.

Transient hyper-17-hydroxyprogesteronemia: a clinical subgroup of patients diagnosed at neonatal screening for congenital adrenal hyperplasia

OBJECTIVE Neonatal screening for congenital adrenal hyperplasia (CAH) is characterized by a high false-positive rate, mainly among preterm and low birth weight infants. The aims of this study were to describe a subgroup of infants with transient serum hyper-17-hydroxyprogesteronemia (hyper-17-OHPemia) and to compare them with false positive and affected by 21-hydroxylase deficiency newborns. METHODS We retrospectively analyzed the clinical data of all newborns positive at CAH neonatal screening, who were referred to our hospital to confirm the diagnosis from 2002 to 2006. They were submitted to clinical investigations and blood tests to evaluate 17-hydroxyprogesterone (17-OHP), renin, and electrolyte levels. CAH-unaffected newborns with increased serum 17-OHP were submitted to strict follow-up monitoring, which included an ACTH-stimulating test and genetic analysis of the 21-hydroxylase gene, until serum 17-OHP decreased. RESULTS Thirty-seven newborns with gestational ages ranging from 33 to 40 weeks were studied. Eight infants (three male and five female) were affected by CAH (serum 17-OHP: 277.5 (210-921) nmol/l), 14 (ten male and four female) were false positives (17-OHP: 3.75 (0.3-8.4) nmol/l), and 15 (ten male and five female) showed a serum hyper-17-OHPemia (17-OHP: 15.9 (9.9-33) nmol/l). No mutations of the 21-hydroxylase gene were found in infants with hyper-17-OHPemia and their serum 17-OHP levels were normalized by the third month of life. CONCLUSION We identified a population of infants with transient serum hyper-17-OHPemia, and no clinical signs of disease or 21-hydroxylase gene mutations. No further investigations are necessary after birth in these newborns if 17-OHP levels decrease, other confirmatory tests such as ACTH-stimulation test or genotyping analysis are necessary only if symptoms appear.

Neonatal hyperglycaemia and abnormal development of the pancreas

Transient and permanent neonatal diabetes mellitus (TNDM and PNDM) are rare conditions occurring in around 1 per 300,000 live births. In TNDM, growth-retarded infants develop diabetes in the first few weeks of life, only to go into remission after a few months with possible relapse to permanent diabetes usually around adolescence or in adulthood. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. The very recently elucidated mutations in KCNJ11 and ABCC8 genes, encoding the Kir6.2 and SUR1 subunits of the pancreatic K(ATP) channel involved in regulation of insulin secretion, account for a third to a half of the PNDM cases. Molecular analysis of chromosome 6 anomalies and the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provides a tool for distinguishing transient from permanent neonatal diabetes mellitus in the neonatal period. Some patients (those with mutations in KCNJ11 and ABCC8) may be transferred from insulin therapy to sulphonylureas.

False biochemical diagnosis of hyperthyroidism in streptavidin-biotin-based immunoassays: the problem of biotin intake and related interferences

Abstract Immunoassays are now commonly used for hormone measurement, in high throughput analytical platforms. Immunoassays are generally robust to interference. However, endogenous analytical error may occur in some patients; this may be encountered in biotin supplementation or in the presence of anti-streptavidin antibody, in immunoassays involving streptavidin-biotin interaction. In these cases, the interference may induce both false positive and false negative results, and simulate a seemingly coherent hormonal profile. It is to be feared that this type of errors will be more frequently observed. This review underlines the importance of keeping close interactions between biologists and clinicians to be able to correlate the hormonal assay results with the clinical picture.

Prevalence of Pituitary Dysfunction After Severe Traumatic Brain Injury in Children and Adolescents: A Large Prospective Study

CONTEXT Traumatic brain injury (TBI) in childhood is a major public health issue. OBJECTIVE We sought to determine the prevalence of pituitary dysfunction in children and adolescents after severe TBI and to identify any potential predictive factors. DESIGN This was a prospective longitudinal study. SETTING The study was conducted at a university hospital. PATIENTS Patients, hospitalized for severe accidental or inflicted TBI, were included. The endocrine assessment was performed between 6 and 18 months after the injury. MAIN OUTCOME MEASURES Basal and dynamic tests of pituitary function were performed in all patients and GH dynamic testing was repeated in patients with low stimulated GH peak (<7 ng/mL). The diagnosis of proven severe GH deficiency (GHD) was based on the association of two GH peaks less than 5 ng/mL on both occasions of testing and IGF-I levels below -2 SD score. Initial cranial tomography or magnetic resonance imaging was analyzed retrospectively. RESULTS We studied 87 children and adolescents [60 males, median age 6.7 y (range 0.8-15.2)] 9.5 ± 3.4 months after the TBI (73 accidental, 14 inflicted). The second GH peak, assessed 4.9 ± 0.1 months after the first evaluation, remained low in 27 children and adolescents. Fifteen patients had a GH peak less than 5 ng/mL (mean IGF-I SD score -1.3 ± 1.5) and five (5.7%) strict criteria for severe GHD. Two children had mild central hypothyroidism and one had ACTH deficiency. We did not find any predictive factors associated with existence of GHD (demographic characteristics, growth velocity, trauma severity, and radiological parameters). CONCLUSION At 1 year after the severe TBI, pituitary dysfunction was found in 8% of our study sample. We recommend systematic hormonal assessment in children and adolescents 12 months after a severe TBI and prolonged clinical endocrine follow-up.

Unexpected high frequency of skeletal dysplasia in idiopathic short stature and small for gestational age patients

OBJECTIVE To assess the prevalence of skeletal dysplasias (SDs) in patients with idiopathic short stature (ISS) or small for gestational age (SGA) status. SETTING Rare Endocrine/Growth Diseases Center in Paris, France. DESIGN A prospective study on consecutive patients with ISS and SGA enrolled from 2004 to 2009. METHOD We used a standardized workup to classify patients into well-established diagnostic categories. Of 713 patients with ISS (n=417) or SGA status (n=296), 50.9% underwent a skeletal survey. We chose patients labeled normal or with a prepubertal slowdown of growth as a comparison group. RESULTS Diagnoses were ISS (16.9%), SGA (13.5%), normal growth (24.5%), transient growth rate slowing (17.3%), endocrine dysfunction (12%), genetic syndrome (8.9%), chronic disease (5.1%), and known SD (1.8%). SD was found in 20.9% of SGA and 21.8% ISS patients and in only 13.2% in our comparison group. SD prevalence was significantly higher in the ISS group than in the comparison group, especially (50%) for patients having at least one parent whose height was <-2 SDS. Dyschondrosteosis and hypochondroplasia were the most frequently identified SD, and genetic anomaly was found in 61.5 and 30% respectively. Subtle SD was found equally in the three groups and require long-term growth follow-up to evaluate the impact on final height. CONCLUSION SD may explain more than 20% of cases of growth retardation ascribed to ISS or SGA, and this proportion is higher when parental height is <-2 SDS. A skeletal survey should be obtained in patients with delayed growth in a context of ISS or SGA.

Inadequate Cortisol Response to the Tetracosactide (Synacthen®) Test in Non-Classic Congenital Adrenal Hyperplasia: An Exception to the Rule?

Aims: To describe cortisol response to tetracosactide and to review the literature on adrenal function in non-classic congenital adrenal hyperplasia (NCCAH) patients. Methods: We compared cortisol responses to tetracosactide (250 μg) between NCCAH patients and a comparison group (CG) of patients with premature pubarche and normal tetracosactide test. An adequate cortisol response was defined as a peak ≥18 μg/dl. Results: We included 35 NCCAH patients (26 girls, 9 boys), whose mean age at testing was 7.0 years (0.8-15.6), and 47 patients in the CG (39 girls, 8 boys), whose mean age was 7.2 years (0.5-9.9). Baseline cortisol was significantly higher in the NCCAH group than in the CG [12.9 (4.3-22.2) vs. 9.7 (4.2-16.2) μg/dl, respectively; p = 0.0006]. NCCAH patients had lower cortisol peak response compared to the CG [18.2 (6.3-40) vs. 24.9 (12-30.3) μg/dl, respectively; p < 0.0001]. Peak cortisol was <18 μg/dl in 21/35 (60%) NCCAH patients versus 1/47 (2.1%) in the CG. No NCCAH patients had acute adrenal insufficiency, but 2 reported severe fatigue that improved with hydrocortisone. Conclusions: The cortisol response to tetracosactide was inadequate (<18 μg/dl) in 60% of patients with NCCAH. Hydrocortisone therapy may deserve consideration when major stress (surgery, trauma, childbirth) or objectively documented fatigue occurs in NCCAH patients with inadequate cortisol response.

Efficacy and Safety of Continuous Subcutaneous Infusion of Recombinant Human Gonadotropins for Congenital Micropenis during Early Infancy

Background: Early postnatal administration of gonadotropins to infants with congenital hypogonadotropic hypogonadism (CHH) can mimic minipuberty, thereby increasing penile growth. We assessed the effects of gonadotropin infusion on stretched penile length (SPL) and hormone levels in infants with congenital micropenis. Methods: Single-center study including 6 males with micropenis in case of isolated CHH (n = 4), panhypopituitarism (n = 1), and partial androgen insensitivity syndrome (PAIS; n = 1). Patients were evaluated at baseline, monthly and at the end of the study through a clinical examination (SPL, testicular position and size), serum hormone assays (testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone [AMH]), and ultrasound of penis/testes. Results: In CHH, significant increases occurred in serum testosterone (from undetectable level to 3.5 ± 4.06 ng/mL [12.15 ± 14.09 nmol/L]), SPL (from 13.8 ± 4.5 to 42.6 ± 5 mm; p < 0.0001), inhibin B (from 94.8 ± 74.9 to 469.4 ± 282.5 pg/mL, p = 0.04), and AMH (from 49.6 ± 30.6 to 142 ± 76.5 ng/mL, p = 0.03). Micropenis was corrected in all patients, except one. On treatment, in the patient with PAIS, SPL was increased from 13 to 38 mm. Conclusions: Early gonadotropin infusion is a safe, well-tolerated and effective treatment. The effect in PAIS has not been reported previously. Long-term follow-up is needed to assess the impact, if any, on future fertility and reproduction.


Erratum. Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations. Diabetes Care 2015;38:2033–2041

The online version reflects these changes. Mutations n of patients; patient no. KCNJ11 G228A n 5 1; 13 E227K n 5 1; 14 E292G n 5 1; 10 H186D n 5 1; 5 I182T n 5 1; 9 Q51G n 5 1; 8 R201C n 5 2; 16, 18 R201H n 5 7; 1, 2, 3, 7, 11, 15, 17 V59M n 5 1; 12 ABCC8 R1183W n 5 1; 4 R1380H n 5 1; 6 Jacques Beltrand, Caroline Elie, Kanetee Busiah, Emmanuel Fournier, Nathalie Boddaert, Nadia Bahi-Buisson, Miriam Vera, Emmanuel Bui-Quoc, Isabelle Ingster-Moati, Marianne Berdugo, Albane Simon, Claire Gozalo, Zoubir Djerada, Isabelle Flechtner, Jean-Marc Treluyer, Raphael Scharfmann, Helene Cavé, Laurence Vaivre-Douret, and Michel Polak, on behalf of the GlidKir Study Group Diabetes Care Volume 39, January 2016 175