Towards the identification of a genetic basis for Landau-Kleffner syndrome.

OBJECTIVE: To establish the genetic basis of Landau-Kleffner syndrome (LKS) in a cohort of two discordant monozygotic (MZ) twin pairs and 11 isolated cases. METHODS: We used a multifaceted approach to identify genetic risk factors for LKS. Array comparative genomic hybridization (CGH) was performed using the Agilent 180K array. Whole genome methylation profiling was undertaken in the two discordant twin pairs, three isolated LKS cases, and 12 control samples using the Illumina 27K array. Exome sequencing was undertaken in 13 patients with LKS including two sets of discordant MZ twins. Data were analyzed with respect to novel and rare variants, overlapping genes, variants in reported epilepsy genes, and pathway enrichment. RESULTS: A variant (cG1553A) was found in a single patient in the GRIN2A gene, causing an arginine to histidine change at site 518, a predicted glutamate binding site. Following copy number variation (CNV), methylation, and exome sequencing analysis, no single candidate gene was identified to cause LKS in the remaining cohort. However, a number of interesting additional candidate variants were identified including variants in RELN, BSN, EPHB2, and NID2. SIGNIFICANCE: A single mutation was identified in the GRIN2A gene. This study has identified a number of additional candidate genes including RELN, BSN, EPHB2, and NID2. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Syndrome hypothénarien du marteau: étiologie peu connue de phénomène de Raynaud secondaire [Hypothenar hammer syndrome: little-known etiology of secondary Raynaud's phenomenon]

Hypothenar hammer syndrome is an uncommonly encountered cause of Raynaud's phenomenon associated with professional or recreational activities. We report 6 consecutive cases seen in our angiology unit between 1988 and 1990. Clinical findings include a history of repeated microtraumatisms of the dominant hand, male sex, unilaterality, sudden onset, and severe Raynaud's phenomenon of the last three fingers. Investigations reveal an aneurysm or thrombosis of the distal cubital artery or of the superficial palmar branch, associated with occlusion of digital arteries. Avoidance of the aggravating conditions or resection and/or plasty of the affected vascular segment usually leads to disappearance of the symptoms.

Molecular Analysis of the PTEN Gene in a Choroidal Schwannoma in the Context of a Hamartomatous Syndrome

Purpose: To investigate the molecular involvement of PTEN, a tumor suppressor gene, in a case of cellular pigmented choroidal Schwannoma in a patient with hamartomatous syndrome due to heterozygous PTEN germline mutation. Methods: Histopathological, immunohistochemical, and electron microscopy analyses were performed by standard procedures. Paraffin-embedded samples of normal and tumor eye tissues were collected and DNA was extracted. A 145 bp region flanking the heterozygous c.406T>C mutation in exon 5 of PTEN was amplified by PCR and sequenced. To evaluate the allelic status of PTEN in the tumor sample, we cloned different PCR products in E. coli using a TA cloning procedure. Results: Histopathology demonstrated a posterior choroidal mass measuring 1.3 x 1.6 x 1.4 cm. The tumor was composed by fascicles of spindle cells with wavy cytoplasm. No Verrocay bodies could be identified. Scattered histiocytes with clear cytoplasm were present. By immunohistochemistry, the cells were expressing S100 and focally Melan A proteins. Pericellular type IV collagen could be demonstrated. Interlacing cytoplasmic processes covered by thick basement membrane could be found by electron microscopy as well as few premelanosomes. Moderate PTEN expression by immunohistochemistry was identified in some cells. As expected, the germline mutation could be detected by DNA sequencing in both the paraffin-embedded normal and tumor eye tissues. Analysis of 33 E. coli colonies bearing clones from the tumor eye tissue DNA surprisingly revealed that most of them contained the PTEN wild-type allele (29 vs. 4, Fisher's test p-value = 0.002). Conclusions: This is the first reported case of choroidal cellular Schwannoma arising in the context of a PTEN hamartomatous syndrome. Allelic analysis of PTEN in the tumor suggests a statistically-significant partial loss of heterozygozity in favor of the wild-type allele. Our findings are in clear contrast with what is usually observed in cancer tissues, for which mutated alleles of tumor suppressor genes are usually brought to homozygosity. Similar results were previously reported in human non-Hodgkin's lymphomas, displaying an overexpression of the wild-type form of the tumor suppressor gene p53. We are in the process of investigating additional DNA derived from other fresh and paraffin-embedded tissues from the patient, in order to gain insights on the molecular bases of PTEN involvement in this rare choroidal Schwannoma.

Syndrome of birt-hogg-dubé, a histopathological pitfall with similarities to tuberous sclerosis: a report of three cases.

: Birt-Hogg-Dubé Syndrome (BHD) is a rare condition, transmitted as an autosomal-dominant trait. The etiology is due to a mutation in the BHD gene, which encodes folliculin (FLCN), located on chromosome 17p. The skin changes observed are benign skin tumors consisting of hamartomas of the hair follicle with dermal changes. Patients with BHD have an increased risk of spontaneous pneumothorax due to rupture of lung cysts and an increased risk of kidney tumors. We report 3 new cases of BHD and discuss their clinical features, histopathological findings, and molecular diagnostics. We highlight the importance of genetic analysis to confirm the diagnosis because of the clinical pitfalls involved in establishing a diagnosis. Finally, we discuss the histopathological features in BHD and tuberous sclerosis complex and focus on their overlapping criterias. A correct diagnosis is essential as it can be life saving for patients.

Lambert-Eaton myasthenic syndrome revealing an abdominal neuroblastoma.

Lambert-Eaton myasthenic syndrome is a paraneoplastic syndrome that may reveal a primitive tumor. Neuroblastoma in children and small cell lung carcinoma in adults are the leading tumors revealed or expressed by paraneoplastic phenomena. The clinical neurologic manifestations of Lambert-Eaton myasthenic syndrome are muscular weakness, sleepiness, absence of reflexes, and dysautonomia. Neurologic manifestations are explained by the induction of an autoimmune response because of the presence of antigens that are expressed by the tumor. Neurologic paraneoplastic disorders may also be the result of toxicity of drugs, coagulopathy, infection, or metabolic diseases. We describe the case of a 13-month-old child with unusual neurologic symptoms because of the presence of an abdominal neuroblastoma.

Familial occurrence of an association of multiple intestinal atresia and choanal atresia: a new syndrome?

We report on two familial cases from a non-consanguineous marriage, presenting multiple intestinal and choanal atresia. Massive hydramnios and dilatation of the bowel were observed at 29 weeks of gestation during routine ultrasound scan of a healthy mother. The fetal karyotype was normal and cystic fibrosis screening was negative. Regular scans were performed throughout the pregnancy. The child was born at 34 weeks gestation. Choanal atresia was diagnosed at birth and abdominal investigations showed multiple atresia interesting both the small bowel and the colon. Further interventions were necessary because of recurrent obstructions. During the following pregnancy, a dilatation of the fetal intestinal tract was detected by ultrasonography at 27 weeks of gestation. Pregnancy was interrupted. Post-mortem examination of the fetus confirmed the stenosis of long segments of the small intestine associated with areas of colonic atresia. In both cases, histology and distribution were consistent with those reported in hereditary multiple intestinal atresia (HMIA). An association between multiple intestinal and choanal atresia has never been reported. We suggest it could correspond to a new autosomal recessive entity for which cytogenetic investigations and high-resolution array CGH revealed no visible anomalies.

Efficacy of in-hospital multidimensional interventions of secondary prevention after acute coronary syndrome: a systematic review and meta-analysis

BACKGROUND: Secondary prevention programs for patients experiencing an acute coronary syndrome have been shown to be effective in the outpatient setting. The efficacy of in-hospital prevention interventions administered soon after acute cardiac events is unclear. We performed a systematic review and meta-analysis to determine whether in-hospital, patient-level interventions targeting multiple cardiovascular risk factors reduce all-cause mortality after an acute coronary syndrome. METHODS AND RESULTS: Using a prespecified search strategy, we included controlled clinical trials and before-after studies of secondary prevention interventions with at least a patient-level component (ie, education, counseling, or patient-specific order sets) initiated in hospital with outcomes of mortality, readmission, or reinfarction rates in acute coronary syndrome patients. We classified the interventions as patient-level interventions with or without associated healthcare provider-level interventions and/or system-level interventions. Twenty-six studies met our inclusion criteria. The summary estimate of 14 studies revealed a relative risk of all-cause mortality of 0.79 (95% CI, 0.69 to 0.92; n=37,585) at 1 year. However, the apparent benefit depended on study design and level of intervention. The before-after studies suggested reduced mortality (relative risk [RR], 0.77; 95% CI, 0.66 to 0.90; n=3680 deaths), whereas the RR was 0.96 (95% CI, 0.64 to 1.44; n=99 deaths) among the controlled clinical trials. Only interventions including a provider- or system-level intervention suggested reduced mortality compared with patient-level-only interventions. CONCLUSIONS: The evidence for in-hospital, patient-level interventions for secondary prevention is promising but not definitive because only before-after studies suggest a significant reduction in mortality. Future research should formally test which components of interventions provide the greatest benefit.