Isabelle Delpierre

Familial CHARGE syndrome because of CHD7 mutation: Clinical intra- and interfamilial variability

CHARGE syndrome (OMIM #214800) is a multiple malformation syndrome with distinctive diagnostic criteria, usually because of CHD7 (chromodomain helicase DNA binding 7) haploinsufficiency. Familial occurrence of CHARGE syndrome is rare. We report six patients from two Caucasian families (both with one parent and two children) affected by mild to severe CHARGE syndrome. Direct sequencing of the CHD7 gene was performed in these two unrelated families. A mutation in exon 8 (c.2501C>T – p.S834F) in first chromodomain was found in family A and a nonsense mutation in exon 2 (c.469C>T – p.R157X) in family B. Both mutations are de novo in the parents. In family A, the elder son had bilateral cleft lip and palate, esophageal atresia with fistula, complex heart defect and vertebral abnormalities, while the younger had a posterior coloboma. Their mother had asymptomatic vestibular dysfunction and retinal coloboma, identified after the molecular diagnosis of her children. In family B, both affected children had severe expression of CHARGE syndrome. The father carrying the mutation only had asymmetric anomaly of the pinnae. These familial reports describe the intrafamilial variability of CHARGE syndrome, and underline the presence of CHD7 mutations in patients who do not fit the ‘classical clinical criteria’ for CHARGE syndrome.

Accurate pre-operative localization of pathological parathyroid glands using 11C-methionine PET/CT.

OBJECTIVE The pre-operative technique most routinely used to localize pathological parathyroid glands (PPG), prior to minimal access surgery (MAS), relies on 99mTc-sestamibi (MIBI) scintigraphy. Positron emission tomography (PET) using the radiolabelled amino acid 11C-methionine as the tracer agent offers a technological alternative to localize PPG. In this study we evaluated the sensitivity of 11C-methionine PET/CT (MET-PET/CT) for PPG detection and the extent to which MET-PET/CT images may contribute to the planning of surgical procedures. DESIGN Thirty patients were included, 22 with primary hyperparathyroidism and eight with secondary hyperparathyroidism. Patients suspected of suffering from parathyroid hyperplasia underwent a complete surgical exploration of the neck region. In those suspected of parathyroid adenoma, surgery was limited to the presumed localization described by MET-PET/CT. To specifically address the additional benefit of the MET-PET/CT in terms of surgical planning and procedure, the surgeon classified the patients into two categories depending on the type of benefit, or the reason for the absence of benefit, occurring in each case. We also compared the sensitivity of MET-PET/CT and MIBI scintigraphy. RESULTS The total number of lesions removed was 46 (24 adenomatous and 22 hyperplastic). Globally, MET-PET/CT provided additional benefit to surgery in 15 out of 30 cases (50%). The sensitivity of 11C-methionine PET/CT and MIBI scintigraphy was respectively 92% and 95% for adenoma, and 68% and 59% for hyperplasia, on the basis of available resected lesions. CONCLUSION MET-PET/CT appears a reliable technique to guide MAS of parathyroid glands.

Ultrasound-guided fine-needle aspiration of thyroid nodules: stratification of malignancy risk using follicular proliferation grading, clinical and ultrasonographic features.

OBJECTIVE To evaluate the diagnostic value of fine-needle aspiration (FNA) cytology and the additive contribution brought by clinical and ultrasound (US) features. METHOD Cytological and histological diagnoses were compared in a series of 924 patients who underwent US-guided FNA before surgery. We additionally developed a grading system for follicular proliferation (FP) FNA diagnosis, and investigated its impact on the malignancy risk as well as the additive contribution of clinical and US features by means of decision tree analysis. RESULTS Excluding FP cases (n=395), our data demonstrated that strictly benign or malignant FNA diagnoses exhibit great concordance with benign or malignant histological diagnoses (97.8% accuracy). Our grading system that was applied to the 395 FP cases revealed that grades 1, 2 and 3 were associated with a 7.7, 17.7 and 45.7% incidence of malignancy respectively. Decision tree analysis resulted in a classification model which involved FP grade, patients age, serum thyroglobulin level, nodule size and nodule uniqueness. This model identified a subgroup of patients with grade 1 FP nodules who were older than 50 years, and who had a higher risk of malignancy (17.9%). In addition, high serum thyroglobulin levels were associated with a very high malignancy risk (75.0%) for patients with grade 3 FP nodules. Finally, among grade 2 FP patients, unique and large nodules were associated with a high malignancy risk of 36.1%. CONCLUSIONS The integration of FP grade, clinical and US features allows the stratification of patients with FP cytology according to their risk of malignancy.

A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease

Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified “de novo” splice site mutation (c.698‐2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient.

Posterior osteosynthesis of the atlas for nonconsolidated Jefferson fractures: a new surgical technique.

Study Design. Case report and surgical technique. Objective. To describe a new technique to treat atlas burst fractures by selectively reconstructing the atlas from a posterior approach. Summary of Background Data. The two surgical techniques reported until now for stabilizing atlas burst fractures are associated with some drawbacks. Posterior C0-C2 or C1-C2 fixations significantly reduce head rotation, while the transoral C1 lateral masses osteosynthesis can be associated with oropharyngeal and neurological complications. We propose a new surgical technique for the treatment of unstable Jefferson fractures aimed at avoiding these problems. Methods. A 25-year-old man presented with a Jefferson type III atlas fracture after a traffic accident. The fracture failed to consolidate after 3 months of halo brace immobilization. Surgery consisted in inserting bilateral posterior C1 lateral mass screws interconnected by a transversal rod, thereby creating a second C1 posterior arch under the fractured one. Results. Postoperative course was uneventful. Immediate postoperative stability was confirmed on dynamic X-ray films and head rotation was preserved. Delayed computed tomography scan demonstrated fracture consolidation. Conclusion. The surgical technique described is new and effective for treating atlas burst fractures. This posterior procedure allows mobility preservation, with a low morbidity rate.

¹⁸F-FDG PET/CT and MRI in the follow-up of head and neck squamous cell carcinoma.

We evaluated the diagnostic performance of (18)F-FDG PET/CT and MRI for the assessment of head and neck squamous cell carcinoma (HNSCC) relapse. Since early treatment might prevent inoperable relapse, we also evaluated THE performance of early unenhanced (18)F-FDG PET/CT in residual tumor detection. The study was prospectively performed on 32 patients who underwent (18)F-FDG PET/CT and MRI before treatment and at 4 and 12 months after treatment. (18)F-FDG PET/CT was also performed 2 weeks after the end of radiotherapy. Histopathology or a minimum of 18 months follow-up were used as gold standard. Before treatment (18)F-FDG PET/CT and MRI detected all primary tumors except for two limited vocal fold lesions (sensitivity 94%). MRI was more sensitive than (18)F-FDG PET/CT for the detection of local extension sites (sensitivity 75 vs 58%), but at the cost of a higher rate of false positive results (positive predictive value 74 vs 86%). For relapse detection at 4 months, sensitivity was significantly higher for (18)F-FDG PET/CT (92%) than for MRI (70%), but the diagnostic performances were not significantly different at 12 months. For the detection of residual malignant tissue 2 weeks post-radiotherapy, sensitivity and specificity of (18)F-FDG PET/CT were respectively 86 and 85% (SUV cut-off value 5.8). (18)F-FDG PET/CT is effective in the differentiation between residual tumor and radiation-induced changes, as early as 2 weeks after treatment of a primary HNSCC. For follow-up, performance of (18)F-FDG PET/CT and MRI are similar except for a higher sensitivity of (18)F-FDG PET/CT at 4 months.

Acute transient thyroid swelling after fine-needle aspiration biopsy: rare complication of unknown origin

Our patient’s plasma normetanephrine and noradrenaline levels did not suppress sufficiently during the test, which was consistent with the presence of phaeochromocytoma. During this test and the initial workup, the patient was not consuming any drugs or medication. Follow-up imaging studies were carried out over the next 12 months and were still negative (Table 1). Genetic testing for phaeochromocytoma was also performed including examination for mutations in ret proto-oncogene (RET), succinate dehydrogenase complex, subunits B,C,D (SDHB/SDHC/SDHD) and von Hippel-Lindau tumour suppressor gene (VHL), which were also negative. In parallel to the medical workup, he was followed by medical psychiatry for his depression, anxiety and physical complaints. Two months after his initial presentation, the antidepressant citalopram was prescribed, but the patient was poorly adherent and did not take the medication. Treatment with fluoxetine was initiated 7 months post-presentation, with better adherence, and titrated up to 30 mg daily. He also underwent occupational and physical therapy. This led to some improvement in his mood, anxiety, somatic complaints and functioning, and a concomitant, progressive drop in his catecholamine levels, which on last measurement had normalized (Table 1). Phaeochromocytoma is a challenging but important diagnosis, with plasma metanephrines being the gold standard for diagnosis. In cases where this is insufficient, a clonidine suppression test is considered the most sensitive and specific additional diagnostic test. This test was introduced to address the problem of how to distinguish patients with phaeochromocytoma from those with false-positive biochemical results. By activating a2-adrenoceptors in the brain and on sympathetic nerve endings, clonidine suppresses noradrenaline release by sympathetic nerves. Therefore, decreases in elevated plasma noradrenaline concentrations after clonidine suggest sympathetic activation, whereas a lack of decrease suggests phaeochromocytoma. This patient had a convincing biochemical profile of phaeochromocytoma which led to an extensive diagnostic imaging workup, which was all negative. During his entire workup, he was followed by medical psychiatry and demonstrated anxiety and depression, which were felt to be secondary to an organic medical condition. However, treating his psychiatric condition with supportive therapy and treatment with a selective serotonin reuptake inhibitor (SSRI) led to marked improvement in his catecholamine production. Unlike tricyclic antidepressants, which are reported to cause a false-positive elevation of catecholamines, the SSRIs are not reported to influence the measurement of catecholamines. Previous reports in adults have shown that an elevation of noradrenaline and dopamine, as in our case, rather than adrenaline, can occur in the setting of anxiety, depression or a bipolar disorder. To our knowledge, no similar data have been reported in children. The patient presented had multiple constitutional complaints and, 2 years after his initial presentation, is still being investigated and treated by a multidisciplinary team and receiving psychiatric treatment. Although all the medical and psychiatric issues have not been fully resolved, it is now clear that catecholamine elevations were false-positives and the ongoing concern of phaeochromocytoma was unwarranted. The elevations resolved with improvement in his psychiatric condition. In conclusion, although depression can be primary or secondary to organic causes, if depression is suspected in the presence of abnormal catecholamine levels, a false-positive result should be considered.

MDCT imaging of traumatic brain injury

The aim of emergency imaging is to detect treatable lesions before secondary neurological damage occurs. CT plays a primary role in the acute setting of head trauma, allowing accurate detection of lesions requiring immediate neurosurgical treatment. CT is also accurate in detecting secondary injuries and is therefore essential in follow-up. This review discusses the main characteristics of primary and secondary brain injuries.

Complications of lumbar puncture in a child treated for leukaemia

Lumbar puncture may lead to neurological complications. These include intracranial hypotension, cervical epidural haematomas, and cranial and lumbar subdural haematomas. MRI is the modality of choice to diagnose these complications. This report documents MRI findings of such complications in a child treated for leukaemia.