Autoimmune cytopenia and Kabuki syndrome in paediatrics: Insights in 11 patients.

Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives.

A focus on dominant negative variants in a series of 170 heterozygous FXI-deficient patients.

INTRODUCTION: Dominant-negative effects have been described for 10 F11 variants in the literature. AIM: The current study aimed at identifying putative dominant-negative F11 variants. MATERIAL AND METHODS: This research consisted in a retrospective analysis of routine laboratory data. RESULTS: In a series of 170 patients with moderate/mild factor XI (FXI) deficiencies, we identified heterozygous carriers of previously reported dominant-negative variants (p.Ser243Phe, p.Cys416Tyr, and p.Gly418Val) with FXI activities inconsistent with a dominant-negative effect. Our findings also do not support a dominant-negative effect of p.Gly418Ala. We also identified a set of patients carrying heterozygous variants, among which five out of 11 are novel, with FXI activities suggesting a dominant-negative effect (p.His53Tyr, p.Cys110Gly, p.Cys140Tyr, p.Glu245Lys, p.Trp246Cys, p.Glu315Lys, p.Ile421Thr, p.Trp425Cys, p.Glu565Lys, p.Thr593Met, and p.Trp617Ter). However, for all but two of these variants, individuals with close to half normal FXI coagulant activity (FXI:C) were identified, indicating an inconstant dominant effect. CONCLUSION: Our data show that for some F11 variants recognized has having dominant-negative effects, such effects actually do not occur in many individuals. The present data suggest that for these patients, the intracellular quality control mechanisms eliminate the variant monomeric polypeptide before homodimer assembly, thereby allowing only the wild-type homodimer to assemble and resulting in half normal activities. In contrast, in patients with markedly decreased activities, some mutant polypeptides might escape this first quality control. In turn, assembly of heterodimeric molecules as well as mutant homodimers would result in activities closer to 1:4 of FXI:C normal range.

Assessment of barium diffusion from therapeutic mud wrapped in micro-perforated polyethylene bags towards the human organism.

Barium is present within the clay-derived therapeutic mud packs deposed on the patient's skin for treating some rheumatologic conditions. We studied in twenty-four young healthy volunteers the diffusion of Ba from mud wrapped in micro-perforated polyethylene bags and soaked in mineral water. No significant systematic increase in plasma or urine Ba levels was evidenced when comparing pre- and post-treatment samples using inductively-coupled plasma mass spectrometry. These levels were markedly inferior to the recommended thresholds in nearly all the participants. Noticeably variability in blood and especially urine Ba concentrations was large and mainly explained by environmental exposure (alimentation). Interestingly, we evidenced an intense Ba accumulation within the therapeutic mud at the end of the regimen. Because we chose a clay with one of the highest Ba content available in France for medical therapy and participants with an optimal transcutaneous diffusion capacity (young individuals with low-fat mass), we conclude unambiguously that there is no risk of Ba overexposure in patients receiving pelotherapy according to the procedure used in French medical spas.

Mortality in the Western Pyrenees during the 18th century. Data from the parish register of the village of Arudy (1741-1800), Bearn, France.

OBJECTIVES: We aimed to determine the public health status of an 18th century mountain locality. METHODS: We collected data registered in parish death certificates from Arudy, a small village in the French Pyrenees during the period 1741-1800. RESULTS: Two thousand and six hundred and sixty-three cases were studied. About 50% of deaths occurred during the first 10 years of life. There were some particularities in deaths pattern with regards to age categories between males and females and seasonality. A fraction of individuals died at advanced ages (24.1% ≥60 years and of note three cases ≥100 years). The cause of death was reported in only 2.2% of cases (nearly always sudden fatalities). Maternal mortality could not be precisely determined. Throughout this period we identified a series of mortality crises which targeted mostly children and were probably in relation with undocumented epidemics. CONCLUSIONS: These data offer some clues about the sanitary situation of an European mountain community during the 18th century.

Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.

A French observational study describing the use of human polyvalent immunoglobulins in hematological malignancy-associated secondary immunodeficiency.

OBJECTIVE: To describe the characteristics of patients suffering from secondary immunodeficiencies (SID) associated with hematological malignancies (HM), who started immunoglobulin replacement therapy (IgRT), physicians' expectations regarding IgRT, and IgRT modalities. METHODS: Non-interventional, prospective French cross-sectional study. RESULTS: The analysis included 231 patients (66 ± 12 years old) suffering from multiple myeloma (MM) (N = 64), chronic lymphoid leukemia (CLL) (N = 84), aggressive non-Hodgkin B-cell lymphoma (aNHL) (N = 32), indolent NHL (N = 39), acute leukemia (N = 6), and Hodgkin disease (N = 6). Of the HM, 47% were currently treated, 42% were relapsing or refractory, 23% of patients had received an autologous hematopoietic stem-cell transplant, and 1% had received an allograft. Serum immunoglobulin trough levels in 195 individuals were less than 5 g/L in 68.7% of cases. Most patients had a history of recurrent infections. Immunoglobulin dose was about 400 mg/kg/mo. Half of patients started with subcutaneous infusion. When starting IgRT, physicians mainly expected to prevent severe and moderate infections. They also anticipated improvement in quality of life and survival which is beyond evidence-based medicine. CONCLUSION: NHL is a frequent condition motivating IgRT besides well-recognized indications. Physicians mainly based the decision of starting IgRT on hypogammaglobulinemia and recurrence of infections but, irrespective of current recommendations, were also prepared to start IgRT prophylactically even in the absence of a history of infections.

[Prescription of physical activity by general practitioners: The Biarritz Côte Basque Sport Santé experience]. / La prescription d'activité physique par le médecin traitant : l'expérience de Biarritz Côte Basque Sport Santé.

INTRODUCTION: Physical inactivity represents a public health challenge because it is associated with an increased risk of chronic disease and premature death. The prescription of physical activity (PA) by general practitioners in the context of sports clubs was used to fight against physical inactivity. METHODS: Since May 2015, the Biarritz Côte Basque Sport Santé (BSS) association has proposed a primary prevention scheme based on physical activity prescribed by a panel of voluntary general practitioners designed for inactive persons with no significant chronic diseases. Participants are referred either directly to a sports club in which they are managed by a trained sports instructor or initially to a BSS sport health educator, who proposes an interview and physical evaluation in order to choose the most appropriate sporting activity. PA (comprising a total of 15 activities) is prescribed for twelve weeks and each participant is evaluated at the end of this period. We report our experience with this programme after the inclusion of 200 individuals. RESULTS: Eighty-six physicians from seventeen sites of the Basque coast area participated in this study. Two hundred persons received a PA prescription (men: 27%, mean age: 54 years, range: 18-80); 20% of them were referred directly to participating sports clubs and 80% were first evaluated by our BSS educator. Aquatic gymnastics was the PA most frequently chosen (23%). The number of affiliated sport clubs increased from seven at the beginning of our project to twenty five at the time of analysis. Twenty-eight sport instructors have now been trained and accredited to manage participants. One hundred and thirty eight subjects have completed the planned twelve-week schedule and have been evaluated: 90% of them continue their sport in the sports club. DISCUSSION: Our experience suggests than general practitioner-based PA referral to well-trained sports club educators is a feasible strategy for managing physically inactive individuals. This protocol comprises an intermediary structure, the BSS unit, which allows evaluation and referral to adapted PA for each participant plus compliance monitoring. However, the long-term efficacy of this programme has yet to be evaluated.

Assessment of cardiovascular risk factors in a Roma community from Southwestern France.

OBJECTIVES: Roma from Central-Eastern Europe experience a reduced life expectancy in comparison with the general population. Predisposing cardiovascular risk factors could be the underlying reason for this. Here for the first time epidemiologic data on the distribution of cardiovascular risk factors in a subgroup of French Roma has been presented. METHODS: A descriptive epidemiological field survey was conducted in the Manouche community of Pau, Southwestern France. Fifty participants were included (17 men and 33 women) all living in caravans. A questionnaire to ask for demographic and health information was used, and biometric measurements were took in order to assess cardiovascular risk factors. RESULTS: Our sample included 18% diabetics, 32% people suffering from hypertension, 28% subjects with hypercholesterolemia, and 34% smokers. The prevalence of overweight and obesity was, respectively, 40% and 38% and that of abdominal obesity 64%. These frequencies were about twice those found in the general French population. CONCLUSION: Although our sample was of limited size, our data suggest that French Manouches express a high-risk profile regarding cardiovascular disease, as has been reported for Roma from various countries. Both intrinsic and environmental factors may explain this.

Artistic representations of short stature, a tentative diagnosis.

Throughout human history, disease-related short stature has represented a source of fascination. Following the recent advances in genetics and molecular biology, several hundreds of possible causes are now to be considered. We present herein a few examples of the diagnosis approach of such cases from art sources (sculptures, paintings or photographs for the most recent periods), associated or not with biographical data, allowing semiological and anthropological analyses. The explored period spans from antic great civilizations to 19th Century Western societies. The palaeopathological diagnosis method is based upon medical approach. It includes a search for possible associated abnormalities and the distinction between proportioned, mainly related to hormonal disorders (particularly growth hormone deficiency), and non-proportioned cases especially associated with genetic skeletal dysplasias. Among this latter category, achondroplasia is the most represented cause of short stature. Other more exceptional etiologies are also reported.

The Basque paradigm: genetic evidence of a maternal continuity in the Franco-Cantabrian region since pre-Neolithic times.

Different lines of evidence point to the resettlement of much of western and central Europe by populations from the Franco-Cantabrian region during the Late Glacial and Postglacial periods. In this context, the study of the genetic diversity of contemporary Basques, a population located at the epicenter of the Franco-Cantabrian region, is particularly useful because they speak a non-Indo-European language that is considered to be a linguistic isolate. In contrast with genome-wide analysis and Y chromosome data, where the problem of poor time estimates remains, a new timescale has been established for the human mtDNA and makes this genome the most informative marker for studying European prehistory. Here, we aim to increase knowledge of the origins of the Basque people and, more generally, of the role of the Franco-Cantabrian refuge in the postglacial repopulation of Europe. We thus characterize the maternal ancestry of 908 Basque and non-Basque individuals from the Basque Country and immediate adjacent regions and, by sequencing 420 complete mtDNA genomes, we focused on haplogroup H. We identified six mtDNA haplogroups, H1j1, H1t1, H2a5a1, H1av1, H3c2a, and H1e1a1, which are autochthonous to the Franco-Cantabrian region and, more specifically, to Basque-speaking populations. We detected signals of the expansion of these haplogroups at ∼4,000 years before present (YBP) and estimated their separation from the pan-European gene pool at ∼8,000 YBP, antedating the Indo-European arrival to the region. Our results clearly support the hypothesis of a partial genetic continuity of contemporary Basques with the preceding Paleolithic/Mesolithic settlers of their homeland.

[Public health in the mountain zone in the nineteenth century. The records of births and deaths in the village of Beost, Ossau valley, Bearn]. / La santé publique en zone de montagne au XIXème siècle. Les registres des naissances et décès du village de Béost, vallée d'Ossau, Béarn.

We report a study on 809 births and 885 deaths collected from the civil registries of the Pyrenean village of Beost, Ossau Valley, Bearn, France, during the entire 19th century. Among the studied parameters, some give us interesting data on the population history. Thus, the rate of mortality under 1 year of age (110,7 per thousand), the global longevity of this population (mean age at death: 45,8 years) and the absence of significant increase in mortality during the winter months and periods of difficulty for food availability argue in favor of a quite satisfactory sanitary level. Nevertheless, the reduced longevity of illegitimate children (nine deaths often before the age of 7) suggests an absence of care for this population category who was socially rejected. Furthermore, the proportion of women dying between 21 and 40 years of age was twice than that of men, which could be explained by maternity-related medical complications. The seasonality of births (and therefore of conceptions) is less typical than in the other mountain populations. Finally, we may note an increased mortality at the end of 1856 due to a cholera epidemic and in 1870 because of small pox.

Evidence of pre-Roman tribal genetic structure in Basques from uniparentally inherited markers.

Basque people have received considerable attention from anthropologists, geneticists, and linguists during the last century due to the singularity of their language and to other cultural and biological characteristics. Despite the multidisciplinary efforts performed to address the questions of the origin, uniqueness, and heterogeneity of Basques, the genetic studies performed up to now have suffered from a weak study design where populations are not analyzed in an adequate geographic and population context. To address the former questions and to overcome these design limitations, we have analyzed the uniparentally inherited markers (Y chromosome and mitochondrial DNA) of ~900 individuals from 18 populations, including those where Basque is currently spoken and populations from adjacent regions where Basque might have been spoken in historical times. Our results indicate that Basque-speaking populations fall within the genetic Western European gene pool, that they are similar to geographically surrounding non-Basque populations, and also that their genetic uniqueness is based on a lower amount of external influences compared with other Iberians and French populations. Our data suggest that the genetic heterogeneity and structure observed in the Basque region result from pre-Roman tribal structure related to geography and might be linked to the increased complexity of emerging societies during the Bronze Age. The rough overlap of the pre-Roman tribe location and the current dialect limits support the notion that the environmental diversity in the region has played a recurrent role in cultural differentiation and ethnogenesis at different time periods.

Exome sequencing reveals germline NPAT mutation as a candidate risk factor for Hodgkin lymphoma.

A strong clustering of Hodgkin lymphoma in certain families has been long acknowledged. However, the genetic factors in the background of familial Hodgkin lymphoma are largely unknown. We have studied a family of 4 cousins with a rare subtype of the disease, nodular lymphocyte predominant Hodgkin lymphoma. We applied exome sequencing together with genome-wide linkage analysis to this family and identified a truncating germline mutation in nuclear protein, ataxia-telangiectasia locus (NPAT) gene, which segregated in the family. We also studied a large number of samples from other patients with Hodgkin lymphoma, and a germline variation leading to the deletion of serine 724 was found in several cases suggesting an elevated risk for the disease (odds ratio = 4.11; P = .018). NPAT is thus far the first gene implicated in nodular lymphocyte predominant Hodgkin lymphoma predisposition.

Social Networks in French Balneotherapy: A Focus on Spa Doctors.

Spa therapy is a medical treatment based on the use of natural mineral water. In France, spa therapy is delivered in spa care facilities (SCF) involving the intervention of several actors (stakeholders). Spa doctors are key stakeholders as they prescribe the treatments, follow spa patients and assess spa therapy with scientific studies. This study aimed to analyze the spa doctors' relationships in order to highlight their role in transferring information to other stakeholders, particularly to spa managers. For that purpose, we used the social network analysis (SNA) method by means of snowball data collection. We sent a questionnaire to all the spa therapy categories of actors. In total, 80 persons answered and declared 397 relationships. Our results, based on the categorization of respondents and of their relationships and on quantitative indicators (density, response rate), show that spa doctors demonstrate a very acceptable density of relations with spa managers and elected local authorities. However, they appear to be poorly involved in relations concerning the strategy and management of SCF, although they are essential actors in ensuring the medical relevance and sustainability of spa therapy. This research is of interest to patients' care as it recommends deeper involvement of spa doctors in the management of SCF in order to optimize access to informational resources, specifically regarding the evolution of treatments in accordance with scientific progress. Our data are of international scope because the organizational model of balneotherapy, based on the cooperation between spa doctors and SCF, is universal.

Fast Track Management of Primary Thyroid Lymphoma in the Very Elderly Patient.

A rapid growing cervical mass mobile while swallowing is the most common clinical presentation of severe thyroid malignancy. A 91-year-old female patient with a history of Hashimoto thyroiditis presented with clinical compressive neck symptoms. The patient had gastric Maltoma diagnosed that was surgically resected thirty years ago. A straightforward process was needed to reach full histological diagnosis and initiate prompt therapy. Ultrasound (US) showed a 67 mm hypoechoic left thyroid mass with reticulated pattern without signs of locoregional invasion. Percutaneous trans isthmic US-guided 18G core needle biopsy (CNB) disclosed diffuse large B cell lymphoma of the thyroid gland. FDG PET revealed two distinct thyroid and gastric foci (both SUVmax 39.1). Therapy was initiated rapidly to decrease clinical symptoms in this aggressive stage III primitive malignant thyroid lymphoma. The prognostic nomogram was calculated by using a seven-item scale, which disclosed a one-year overall survival rate of 52%. The patient underwent three R-CVP chemotherapy courses, then refused further treatment and died within five months. Real-time US-guided CNB approach led to rapid patient's management that was tailored to patient's characteristics. Transformation of Maltoma into diffuse large B cell lymphoma (DLBCL) into two body areas is deemed to be extremely rare.

Transfusional iron overload in heavily transfused patients: Real-life data from a 10-year retrospective study of 611 cases managed in a French general hospital.

OBJECTIVES: Epidemiological studies on transfusional iron overload (TIO) in the general population of heavily transfused patients are scarce. The aim of this work was to provide a picture on the distribution and management of this complication within the context of unselected individuals attending a general hospital. METHODS: We retrospectively assessed the characteristics of 611 patients from a single institution having received at least 20 red blood cell (RBC) units over a 10-year period. RESULTS: About two-thirds of these individuals were males and their median age at the 20th RBC was 72years (range: 10-98). Myelodysplastic syndromes (MDS) and acute myeloid leukemia represented the most frequent underlying conditions (53%) but lymphoid malignancies and solid malignancies accounted for 13.6 and 7.3% respectively. In the vast majority of cases various comorbidities (range: 1-6 per patient) were registered including especially cardiovascular disorders. The highest cumulative RBC numbers were observed in MDS patients. Serum ferritin was assessed in 451 patients (73.8%) and ≥1000µg/L in 250 cases, ≥2000µg/L in 100 cases and ≥2500µg/L in 71 cases. Only 97 patients (15.9%) received a treatment for TIO using either a chelator (n=93) or phlebotomy (n=4). CONCLUSION: TIO is not limited to MDS or hemoglobin disorders. Its assessment and management are suboptimal in clinical practice. The ratio of patients receiving iron chelation is markedly lower than theoretically expected mainly because of comorbidities or drug intolerance.