Biomedical subjects
Publications and source records attributed to Francis Brunelle.
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Congenital hyperinsulinism (CHI), characterized by profound hypoglycaemia related to inappropriate insulin secretion, may be associated histologically with either diffuse insulin hypersecretion or focal adenomatous hyperplasia, which share a similar clinical presentation, but result from different molecular mechanisms. Whereas diffuse CHI is of autosomal recessive, or less frequently of autosomal dominant, inheritance, focal CHI is sporadic. The most common mechanism underlying CHI is dysfunction of the pancreatic ATP-sensitive potassium channel (K(+)(ATP)). The two subunits of the K(+)(ATP) channel are encoded by the sulfonylurea receptor gene (SUR1 or ABCC8) and the inward-rectifying potassium channel gene (KIR6.2 or KCNJ11), both located in the 11p15.1 region. Germ-line, paternally inherited, mutations of the SUR1 or KIR6.2 genes, together with somatic maternal haplo-insufficiency for 11p15.5, were shown to result in focal CHI. Diffuse CHI results from germ-line mutations in the SUR1 or KIR6.2 genes, but also from mutations in several other genes, namely glutamate dehydrogenase (with associated hyperammonaemia), glucokinase, short-chain L-3-hydroxyacyl-CoA dehydrogenase, and insulin receptor gene. Hyperinsulinaemic hypoglycaemia may be observed in several overlapping syndromes, such as Beckwith-Wiedemann syndrome (BWS), Perlman syndrome, and, more rarely, Sotos syndrome. Mosaic genome-wide paternal isodisomy has recently been reported in patients with clinical signs of BWS and CHI. The primary causes of CHI are genetically heterogeneous and have not yet been completely unveiled. However, secondary causes of hyperinsulinism have to be considered such as fatty acid oxidation deficiency, congenital disorders of glycosylation and factitious hypoglycaemia secondary to Munchausen by proxy syndrome.
New generation multislice CT technology has changed the approach to non-invasive assessment of congenital heart disease, in both paediatric and adult patients. This is mainly because of rapid advances in spatial and temporal resolution and in post-processing capability. At Hôpital Necker-Enfants Malades, CT with multiplanar and three-dimensional reconstruction has become a routine examination in the evaluation of congenital heart disease planning surgery, complex interventional catheterisations and for follow-up. It has proved to be an invaluable diagnostic and decision-aiding methodology in these situations, as a complement to echocardiography and, increasingly, as a substitute for diagnostic angiography (which is usually associated with higher-dose radiation and longer sedation times, as well as occasional morbidity). This review illustrates the current status of 64-slice CT in congenital heart diseases, including assessment of the aorta, the coronary arteries, the pulmonary arteries, the systemic and pulmonary veins, and other intra- and extracardiac malformations.
BACKGROUND: Congenital hyperinsulinism (CHI) is associated with focal hyperplasia of endocrine tissue in 40-65% of patients. Focal CHI is sporadic and is caused by a germline, paternally inherited, mutation of the SUR1 (ABCC8) or KIR6.2 (KCNJ11) genes (encoding subunits of the pancreatic ATP-dependent potassium channel) together with somatic maternal haploinsufficiency for 11p15.5. Plurifocal or large forms of focal CHI are a cause of apparent failure of surgery, and their underlying mechanism has not been thoroughly investigated. PATIENTS: We here report two patients with bifocal CHI as evidenced by relapsing hypoglycemia after removal of the first focal lesion and the detection of a second, distinct, focal adenomatous hyperplasia during later surgery (patients 1 and 2) and a patient with a giant focal lesion involving the major part of the pancreas (patient 3). RESULTS: In the three patients, a germline, paternally inherited, mutation of SUR1 was found. In patients 1 and 2, haploinsufficiency for the maternal 11p15.5 region resulted from a somatic deletion specific for each of the focal lesions, as shown by the diversity of deletion break points. In patient 3, an identical somatic maternal 11p15 deletion demonstrated by similar break points was shown in two independent lesion samples, suggesting a very early event during pancreas embryogenesis. CONCLUSION: Individual patients with focal hyperinsulinism may have more than one focal pancreatic lesion due to separate somatic maternal deletion of the 11p15 region. These patients and those with solitary focal lesions may follow the two-hit model described by Knudson. The stage of embryogenesis at which the somatic event occurs may account for the observed histological diversity (early event giant lesion, later event small lesion).
The most common clinical sign of autism spectrum disorders (ASD) is social interaction impairment, which is associated with communication deficits and stereotyped behaviors. Based on recent brain-imaging results, our hypothesis is that abnormalities in the superior temporal sulcus (STS) are highly implicated in ASD. STS abnormalities are characterized by decreased gray matter concentration, rest hypoperfusion and abnormal activation during social tasks. STS anatomical and functional anomalies occurring during early brain development could constitute the first step in the cascade of neural dysfunction underlying ASD. We will focus this review on the STS, which has been highly implicated in social cognition. We will review recent data on the contribution of the STS to normal social cognition and review brain-imaging data implicating this area in ASD. This review is part of the INMED/TINS special issue "Nature and nurture in brain development and neurological disorders", based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).
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CONTEXT: Congenital hyperinsulinism (HI) is characterized by hypoglycemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation, but their treatment is dramatically different. Preoperative differential diagnosis was based on pancreatic venous sampling, a technically demanding technique. OBJECTIVE: Positron emission tomography (PET) after injection of [18F]fluoro-L-DOPA (L-dihydroxyphenylalanine) has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]fluoro-L-dopa into dopamine by DOPA decarboxylase. We propose to validate this test by immunohistochemical approach. PATIENTS AND METHODS: Pancreatic surgical specimens of four focal and three diffuse HI were studied, using anti-DOPA decarboxylase and proinsulin antibodies. The effect of an inhibitor of DOPA decarboxylase (carbidopa) on insulin secretion was evaluated in vivo and in cultured INS-1 cells. RESULTS: Immunohistochemical detection of DOPA decarboxylase showed diffuse staining of Langerhans islets in the whole pancreas in all diffuse cases, in contrast with dense focal staining in all focal cases. Staining of Langerhans islets outside the focal lesion was diffusely but weakly positive. We correlated the localization of DOPA decarboxylase and proinsulin in normal pancreas and in both diffuse and focal HI tissues. The diffuse PET uptake found before treatment in one child with diffuse HI disappeared completely after carbidopa administration, suggesting in vivo that pancreatic cells can take up amine precursors and contain DOPA decarboxylase. The insulin secretion measured in the supernatant was the same whether INS-1 cells were treated by dopamine or Lodosyn or untreated. CONCLUSION: We validate PET with as a consistent test to differentiate diffuse and focal HI.
Extramedullary hematopoiesis affects about 15% of the patients treated for thalassemia intermedia. Usually seen in adulthood, the most common location is the paraspinal region. Diagnosis and treatment of extramedullary hematopoiesis located in the pelvis of a young 15-year-old girl is discussed. The young age of the patient and the uncommon site of the mass first lead to the diagnosis of an ovarian dermoid cyst. Because of the clinical history and the typical feature on computed tomography scan, extramedullary hematopoiesis was concluded. A specific treatment based on blood transfusion and hydroxyurea was first proposed but remained inefficient. Surgical excision was thus successfully performed. Whereas surgery is limited to spinal cord compression in paraspinal extramedullary hematopoiesis, this observation argues for surgical treatment in symptomatic intraabdominal extramedullary hematopoiesis when medical treatment fails.
BACKGROUND: There are numerous causes of bilateral hyperechoic kidneys. Congenital disorders of glycosylation (CDGs) are a rapidly growing family of inherited disorders due to defects in the synthesis of the glycans of glycoproteins or other glycoconjugates. OBJECTIVE: To describe renal sonographic abnormalities in CDG type I in infants and children. MATERIAL AND METHODS: A retrospective study of renal US in 12 infants and children: 8 CDG-Ia (6 multivisceral forms, 2 neurological forms), 2 CDG-Ib, and 2 CDG-Ix, with detailed functional renal tests in 6. Histology of the kidneys of one 35-week fetus with CDG-Ia was available. RESULTS: Renal US was normal in the two children with the neurological form of CDG-Ia. All patients with the multivisceral form of CDG-Ia or with CDG-Ib showed increased cortical echogenicity, and/or abnormal pyramids (small +/- hyperechoic). The two patients with CDG-Ix showed predominant involvement of the medulla, with inverted corticomedullary differentiation in one. Kidney size was normal in all but two patients. The fetal kidneys exhibited diffuse microcysts arising from the distal tubules. CONCLUSIONS: Hyperechoic kidneys are common in CDG-I patients, contrasting with grossly preserved renal function. The US pattern seems to differ slightly according to the type of CDG-I, and is consistent with microcystic changes of the renal parenchyma, which occur prenatally, and may be due to ciliary dysfunction secondary to altered glycosylation of tubular glycoproteins. CDG-I, which remains largely underdiagnosed at present, should be added to the causes of hyperechoic kidneys in children, especially in cases of multivisceral involvement, after ruling out other more frequent causes.
INTRODUCTION: Chiari malformation (CM) is a frequent finding in multisutural and syndromic craniosynostosis, occurring in 70% of patients with Crouzon's syndrome, 75% with oxycephaly, 50% with Pfeiffer's syndrome and 100% with the Kleeblattschädel deformity. The pathogenesis of this condition and rationale for treatment are still controversial. DISCUSSION: Since its first description in 1972, several factors have been cited to play a role in inducing CM. In the light of recent publications, the roles of premature fusion of cranial vault and cranial base sutures, of congenital anomalies of the cerebellum and brain stem, of raised intracranial pressure, of venous hypertension and of hydrocephalus are reviewed. Evaluation and management of CM are also discussed. CONCLUSION: Chiari malformation appears to be an acquired and progressive condition that develops in the first months of life, because of a disproportion between hindbrain growth and an abnormally small posterior fossa, a consequence of the premature fusion of lambdoid and cranial base sutures. Venous hypertension caused by stenosis of the jugular foramen can also be present in these patients, resulting in intracranial hypertension and/or hydrocephalus. Careful MRI evaluation is recommended for the forms of craniosynostosis at a high risk of developing hindbrain herniation. The selection of posterior cranial vault expansion as the first surgical procedure is advocated. In selected cases, treatment of the posterior cranial deformity by occipital vault remodelling and treatment of the Chiari-like deformity by suboccipital decompression can be carried out using the same surgical procedure.
Two independent studies have described bilateral temporal hypoperfusion in autistic children. Temporal regions are implicated in social perception, language, and "theory-of-mind," abilities that are impaired in autism. We investigated a putative relationship between cerebral blood flow (rCBF) measured at rest and clinical profile of 45 autistic children (Autism Diagnostic Interview-Revised [ADI-R] scores). A whole-brain covariance analysis was performed. Significant negative correlation was observed between rCBF and ADI-R score in the left superior temporal gyrus. The more severe the autistic syndrome, the more rCBF is low in this region, suggesting that left superior temporal hypoperfusion is related to autistic behavior severity.
New metabolic diseases are regularly identified by a genetic or biochemical approach. Indeed, the metabolic diseases result from an enzymatic block with accumulation of a metabolite upstream to the block and deficit of a metabolite downstream. The characterization of these abnormal metabolites by MRI spectroscopy permitted to identify the deficient enzyme in two new groups of diseases, creatine deficiencies and polyol anomalies. Creatine deficiency is implicated in unspecific mental retardation. A low peak of creatine at MRI spectroscopy is evocating of creatine deficiency which is treatable by creatine administration. Deficiency of synthesis of polyols, metabolites on the pentose pathway, represent new described metabolic diseases with variable symptoms including a neurological distress, liver disease, splenomegaly, cutis laxa and renal insufficiency. The deficit of ribose-5-phosphate isomerase, one of the enzymes whose diagnosis is evoked in front of the accumulation of ribitol, arabitol and xylitol leads to a leucodystrophy in adults. This new deficit was highlighted by the identification of an abnormal peak in cerebral MRI-spectroscopy corresponding to the abnormal accumulation of polyols in brain. Congenital hyperinsulinism (HI) is characterized by profound hypoglycaemia related to inappropriate insulin secretion. Focal and diffuse forms of hyperinsulinism share a similar clinical presentation but their treatment is dramatically different. Until recently, preoperative differential diagnosis was based on pancreatic venous sampling, an invasive and technically demanding technique. Positron emission tomography (PET) after injection of [18F]Fluoro-L-DOPA has been evaluated for the preoperative differentiation between focal and diffuse HI, by imaging uptake of radiotracer and the conversion of [18F]Fluoro-L-DOPA into dopamine by DOPA decarboxylase. PET with [18F]Fluoro-L-DOPA has been validated as a reliable test to differentiate diffuse and focal HI and is now a major differential diagnosis tool in infantile hyperinsulinemic hypoglycaemia.
BACKGROUND: 'Autistic savants' are individuals with autism who have extraordinary skills. Brain mechanisms underlying such capacities are still unknown. AIMS: To map the exceptional calendar capacity of a man with primary autism. METHOD: Positron emission tomography was used to map brain activity in a man who is able to associate a day of the week with the corresponding calendar date. RESULTS: During the calendar task, the left hippocampus, the left frontal cortex and the left middle temporal lobe were activated. CONCLUSIONS: The cerebral circuit involved in this man's prodigious calendar skill is similar to that normally involved in memory retrieval tasks. These results suggest that the prodigious capacities may be sustained by memory processing.
Clinical history and inappropriate insulin secretion during hypoglycemic episodes permit the diagnosis of hyperinsulinism. We report 2 cases of factitious hyperinsulinism leading to partial pancreatectomy. Case 1 was an 8-year-old girl who presented with severe hypoglycemia and elevated insulin and C-peptide levels. Catheterization of pancreatic veins was performed to localize the excess insulin secretion. Insulinoma was suspected, and partial pancreatectomy was performed. Ten days after surgery, severe hypoglycemia recurred with severely elevated plasma insulin levels (x100) but very low C-peptide plasma levels, suggesting factitious hyperinsulinemia. Hypoglycemic episodes before surgery were provoked by oral sulfonamides; postoperative episodes were caused by parenteral insulin. Falsified prescriptions for sulfonamides and insulin by the mother, a nurse, were found. Case 2 was a 6-month-old girl who presented with seizures and hypoglycemia but had a symptom-free interval of many months afterward. At 2 years of age, repeated hypoglycemic seizures and elevated insulin plasma levels suggested congenital hyperinsulinism. C-peptide plasma level, measured once, was normal, but blood sampling was performed 15 minutes after a hypoglycemic episode. Partial pancreatectomy was performed. Two weeks after surgery, hypoglycemic seizures recurred, and the patient was admitted for pancreatic vein catheterization. This investigation was performed during hypoglycemia and revealed high insulin levels and undetectable C-peptide levels, suggesting factitious hypoglycemia. Insulin/C-peptide ratio analysis is crucial to assess factitious hypoglycemia, although sulfonamide-induced hypoglycemia is not thereby detected. One percent (2 of 250) of all cases of hyperinsulinemic hypoglycemia in our unit have been identified as Munchausen syndrome by proxy. Atypical disease history should raise the question of factitious hypoglycemia.
OBJECT: The authors discuss the indications for and timing of a diagnostic neurosurgical procedure in children with diabetes insipidus (DI) and a thickened pituitary stalk (TPS) on magnetic resonance (MR) imaging. METHODS: Seven children with a TPS who presented with DI eventually underwent surgery for diagnostic purposes. The ages at onset of DI were 6 to 16 years, and the follow-up period until surgery was 26.9 +/- 11.9 months. In four of seven children, the stalk appeared normal on the first MR image, but it was thickened and variably enhancing on later images in all instances. The reason for eventual surgery was endocrinological deterioration in two of seven children, radiological progression in two children, and a combination of the two in three children. Three children experienced visual disturbances and four children had optic nerve, chiasma, or hypothalamus involvement. All children suffered additional endocrinological abnormalities pursuant to the initial DI. A definitive diagnosis was achieved in six of seven children: germinomas in five and Langerhans cell histiocytosis in one. One child had lymphocytic infiltrate. None of the children deteriorated neurologically or endocrinologically after the operation. On follow up, vision deficit was irreversible in all children who demonstrated visual abnormalities before treatment. CONCLUSIONS: Surgery should be performed in children with a TPS and DI for early diagnosis and disease-oriented therapy when there is further endocrinological, radiological, or clinical deterioration. The complication rate is low in open biopsies, and histological diagnosis is achieved in most of the cases. All children who present with central DI must undergo head MR imaging, and even if results are normal, close radiological and clinical follow up is mandatory.
UNLABELLED: Hyperinsulinism (HI) of infancy is a neuroendocrine disease secondary to either focal adenomatous hyperplasia or a diffuse abnormality of insulin secretion of the pancreas. HI with focal lesions can revert by selective surgical resection in contrast to the diffuse form, which requires subtotal pancreatectomy when resistant to medical treatment. Neuroendocrine diseases are a heterogeneous group of entities with the ability to take up amine precursors and to convert them into biogenic amines. Therefore, the aim of this study was (a) to evaluate the use of PET with 18F-fluoro-L-dihydroxyphenylalanine (18F-fluoro-L-DOPA) and (b) to distinguish between focal and diffuse HI. METHODS: Fifteen patients (11 boys, 4 girls) with neonatal HI were enrolled in this study. All patients fasted for at least 6 h before the PET examination and their medication was discontinued for at least 72 h. The examination was performed under light sedation (pentobarbital associated with or without chloral). The dynamic acquisition started 45-65 min after the injection of 18F-fluoro-L-DOPA (4.0 MBq/kg weight). Four or 6 scans of 5 min each (2 or 3 steps according to the height of the patient) were acquired from the neck to the upper legs. RESULTS: An abnormal focal pancreatic uptake of 18F-fluoro-L-DOPA was observed in 5 patients, whereas a diffuse uptake of the radiotracer was observed in the pancreatic area of the other patients. All patients with focal radiotracer uptake and also 4 of 10 patients with pancreatic diffuse radiotracer accumulation, unresponsive to medical treatment, underwent surgery. The histopathologic results confirmed the PET findings--that is, focal versus diffuse HI. CONCLUSION: The results of this study suggest that 18F-fluoro-L-DOPA could be an accurate noninvasive technique to distinguish between focal and diffuse forms of HI.
BACKGROUND AND PURPOSE: Mitochondrial dysfunction has been reported in HIV-negative children perinatally exposed to zidovudine, a drug often used in HIV-seropositive mothers during pregnancy. The purpose of this study was to determine the incidence of cerebral MR imaging findings in HIV-uninfected children exposed to zidovudine who present with unexplained neurologic symptoms. METHODS: Two expert groups conducted a systematic, retrospective review of all cerebral MR images available in a multicentric, nationwide French prospective cohort of children born to HIV-seropositive mothers to identify imaging abnormalities. Experts were blinded to each others' interpretations, to the children's neurologic symptoms, and to laboratory evidence of mitochondrial dysfunction. The incidence of abnormalities was determined and compared with the neurologic presentation and laboratory evidence of mitochondrial dysfunction. RESULTS: MR images from 49 HIV-uninfected children (mean age, 26 months) were available for study. All children were perinatally exposed to zidovudine. Twenty-two had probable or established mitochondrial dysfunction according to their symptoms and laboratory data. Twenty-seven children without mitochondrial dysfunction presented with unexplained neurologic symptoms (n = 14) or nonneurologic symptoms (n = 7), and six were asymptomatic. Sixteen of 22 MR images in children with mitochondriopathy were considered abnormal in both independent analyses. Diffuse hyperintensity in the supratentorial white matter (n = 9) and in the tegmentum pons (n = 9) were the most frequent anomalies. Imaging abnormalities were often multifocal (n = 10) and sometimes associated with necrotic areas (n = 3) and volume loss (n = 8). Although 19 of 27 MR images of children without mitochondrial dysfunction were mainly normal, abnormal images were observed in five of 14 children with unexplained neurologic symptoms and in three of six asymptomatic children. CONCLUSION: Images observed in children with antiretroviral-induced mitochondrial dysfunction are similar to those observed in congenital mitochondrial diseases. These images were also observed in symptomatic or asymptomatic children without evidence of systemic mitochondrial dysfunction.
Impairments in social interaction are a key feature of autism and are associated with atypical social information processing. Here we report functional magnetic resonance imaging (fMRI) results showing that individuals with autism failed to activate superior temporal sulcus (STS) voice-selective regions in response to vocal sounds, whereas they showed a normal activation pattern in response to nonvocal sounds. These findings suggest abnormal cortical processing of socially relevant auditory information in autism.