Diagnostic challenges in a child with early onset desmoplastic medulloblastoma and homozygous variants in MSH2 and MSH6

International audienceConstitutional mismatch repair deficiency (CMMRD) is an autosomal recessively inherited childhood cancer susceptibility syndrome caused by biallelic germline mutations in one of the mismatch repair (MMR

Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendation for molecular testing and management

International audienceSHORT syndrome has historically been defined by its acronym: short stature (S), hyperextensibility of joints and/or inguinal hernia (H), ocular depression (O), Rieger abnormality (R) and teething delay (T). More recently several research groups have identified PIK3R1 mutations as responsible for SHORT syndrome. Knowledge of the molecular etiology of SHORT syndrome has permitted a reassessment of the clinical phenotype. The detailed phenotypes of 32 individuals with SHORT syndrome and PIK3R1 mutation, including eight newly ascertained individuals, were studied to fully define the syndrome and the indications for PIK3R1 testing. The major features described in the SHORT acronym were not universally seen and only half (52%) had 4 or more of the classic features. The commonly observed clinical features of SHORT syndrome seen in the cohort included IUGR \textless 10(th) percentile, postnatal growth restriction, lipoatrophy and the characteristic facial gestalt. Anterior chamber defects and insulin resistance or diabetes were also observed but were not as prevalent. The less specific, or minor features of SHORT syndrome include teething delay, thin wrinkled skin, speech delay, sensorineural deafness, hyperextensibility of joints and inguinal hernia. Given the high risk of diabetes mellitus, regular monitoring of glucose metabolism is warranted. An echocardiogram, ophthalmological and hearing assessments are also recommended

Will students pass a competitive exam that they failed in their dreams?

a b s t r a c t We tested whether dreams can anticipate a stressful exam and how failure/success in dreams affect next-day performance. We collected information on students' dreams during the night preceding the medical school entrance exam. Demographic, academic, sleep and dream characteristics were compared to the students' grades on the exam. Of the 719 respondents to the questionnaire (of 2324 total students), 60.4% dreamt of the exam during the night preceding it. Problems with the exam appeared in 78% of dreams and primarily involved being late and forgetting answers. Reporting a dream about the exam on the preexam night was associated with better performance on the exam (p = .01). The frequency of dreams concerning the exam during the first term predicted proportionally higher performance on the exam (R = 0.1, p = .01). These results suggest that the negative anticipation of a stressful event in dreams is common and that this episodic simulation provides a cognitive gain

MSI/MMR-deficient tumor diagnosis: Which standard for screening and for diagnosis? Diagnostic modalities for the colon and other sites: Differences between tumors

International audienceMicrosatellite instability (MSI), which is caused by deficiency of the DNA mismatch repair (MMR) system, is the molecular abnormality observed in tumors associated with Lynch syndrome. Lynch syndrome represents one of the most frequent conditions of cancer predisposition in human, thus requiring specific care and genetic counseling. Moreover, research has recently focused increasingly on MMR deficiency due to its positive predictive value for the efficacy of immune checkpoints inhibitors (ICKi) in metastatic tumors, regardless of their primary origin. MSI has also been demonstrated to constitute an independent prognostic factor in several tumor types, being also associated with alternative response to chemotherapy. These observations have led many professional medical organizations to recommend universal screening of all newly diagnosed colorectal cancers for dMMR/MSI status and increasing evidence support the evaluation of MSI in all human tumors regardless of the cancer tissue of origin. Currently, two standard reference methods, namely immunohistochemistry and polymerase chain reaction, are recommended for the detection of dMMR/MSI status. These methods are equally valid as the initial screening test for dMMR/MSI in colorectal cancer. To date, there is no recommendation for the detection of dMMR/MSI in other primary tumors. In this review, we will present a comprehensive overview of the methods used for evaluation of tumor dMMR/MSI status in colorectal cancer, as well as in other tumor sites. We will see that the evaluation of this status remains challenging in some clinical settings, with the need to improve the above methods in these specific contexts

Hypoglycaemia revealing heterozygous insulin receptor mutations.

International audienceMajor hyperinsulinemia, acanthosis nigricans, impaired glucose tolerance and ovarian hyperandrogenism characterize Type A insulin resistance (IR) syndrome due to dominant-negative heterozygous mutations in the insulin receptor gene (INSR). However, two unrelated families have been described with symptomatic hypoglycemia due to heterozygous INSR p.Arg1201 substitutions in the tyrosine kinase domain. In these patients, major hyperinsulinemia together with decreased insulin clearance was suggested to rescue genetically-altered insulin signalling in vivo in liver and/or muscle. We broaden the genetic spectrum of this rare phenotype of Type A insulin resistance by reporting the observations of two patients with INSR p.Met1180Val or p.Arg1201Gln heterozygous mutations revealed by repeated symptomatic hypoglycemia. Our observations further demonstrate that hyperinsulinemic hypoglycemia in adults can reveal different heterozygous mutations in the insulin receptor tyrosine kinase domain, whether associated or not with acanthosis nigricans, impaired glucose tolerance and/or ovarian hyperandrogenism

Two Decades after Mandibuloacral Dysplasia Discovery: Additional Cases and Comprehensive View of Disease Characteristics

International audiencePathogenic variants in the LMNA gene cause a group of heterogeneous genetic disorders, called laminopathies. In particular, homozygous or compound heterozygous variants in LMNA have been associated with “mandibuloacral dysplasia type A” (MADA), an autosomal recessive disorder, characterized by mandibular hypoplasia, growth retardation mainly postnatal, pigmentary skin changes, progressive osteolysis of the distal phalanges and/or clavicles, and partial lipodystrophy. The detailed characteristics of this multisystemic disease have yet to be specified due to its rarity and the limited number of cases described. Here, we report three unrelated Egyptian patients with variable severity of MAD features. Next-generation sequencing using a gene panel revealed a homozygous c.1580G>A-p.Arg527His missense variant in LMNA exon 9 in an affected individual with a typical MADA phenotype. Another homozygous c.1580G>T-p.Arg527Leu variant affecting the same amino acid was identified in two additional patients, who both presented with severe manifestations very early in life. We combined our observations together with data from all MADA cases reported in the literature to get a clearer picture of the phenotypic variability in this disease. This work raises the number of reported MADA families, argues for the presence of the founder effect in Egypt, and strengthens genotype–phenotype correlations

Syndromes d’insulino-resistance majeure : clinique et physiopathologie

La résistance à l’insuline est une anomalie métabolique fréquente. Elle joue un rôle important dans le syndrome métabolique (ou syndrome X), le diabète de type 2, l’obésité, les syndromes lipodystrophiques plus récemment individualisés survenant au cours des traitements antiviraux de la maladie VIH, et représente un risque cardio-vasculaire préoccupant. Cependant sa physiopathologie reste mal comprise dans ces situations. Les syndromes d’insulino-résistance majeure, bien que rares, permettent d’explorer les mécanismes des altérations de la transmission du message insulinique. Si des mutations du gène du récepteur de l’insuline ont ainsi été mises en évidence chez de rares patients, des altérations post-récepteur sont probablement en cause dans d’autres cas. De plus, le rôle de la répartition corporelle du tissu adipeux semble déterminant dans l’apparition de l’insulino-résistance, comme en témoigne le tableau clinique des lipodystrophies, congénitales ou acquises. Cependant, les deux syndromes lipodystrophiques dont la cause moléculaire est connue (la lipodystrophie familiale partielle de Dunnigan, due à des mutations du gène de la lamine A/C, et la lipodystrophie congénitale généralisée liée à des altérations de la seipine), ont encore une physiopathologie mystérieuse. En effet, la lamine A/C est une protéine nucléaire ubiquitaire, dont d’autres altérations conduisent à une myopathie squelettique et/ou cardiaque. Quant à la seipine, d’expression cérébrale prédominante, ses fonctions sont encore inconnues. Les avancées dans la compréhension de ces syndromes, en particulier les lipodystrophies qui peuvent être considérées comme des syndromes métaboliques caricaturaux, permettront probablement d’éclaicir la physiopathologie de l’insulino-résistance plus commune

Lipodystrophic syndromes: From diagnosis to treatment

International audienceLipodystrophic syndromes are acquired or genetic rare diseases, characterised by a generalised or partial lack of adipose tissue leading to metabolic alterations linked to strong insulin resistance. They encompass a variety of clinical entities due to primary defects in adipose differentiation, in the structure and/or regulation of the adipocyte lipid droplet, or due to immune-inflammatory aggressions, chromatin deregulations and/or mitochondrial dysfunctions affecting adipose tissue. Diagnosis is based on clinical examination, pathological context and comorbidities, and on results of metabolic investigations and genetic analyses, which together determine management and genetic counselling. Early lifestyle and dietary measures focusing on regular physical activity and avoiding excess energy intake are crucial. They are accompanied by multidisciplinary follow-up adapted to each clinical form. In case of hyperglycemia, antidiabetic medications, with metformin as a first-line therapy in adults, are used in addition to lifestyle and dietary modifications. When standard treatments have failed to control metabolic disorders, the orphan drug metreleptin, an analog of leptin, can be effective in certain forms of lipodystrophy syndrome. Metreleptin therapy indications, prescription and monitoring were recently defined in France, representing a major improvement in patient care