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Marfan or associated syndromes (MFS) are some rare genetic diseases leading to a multisystem damage related to connective tissue fragility. Chronic fatigue and decreased physical endurance are almost constant complaints of patients with MFS. Muscle mass worsens through adolescence, which could explain the bone-mass deficit observed in this population. We hypothesize that a personalized exercise rehabilitation program will improve fitness and quality of life (QoL) of these patients. Self-controlled study with a 6-month home-based cyclo-ergometer and muscular strengthening personalised rehabilitation program based on first ventilatory-threshold. Baseline evaluation was performed 3 months prior to the start of the rehabilitation program, then at the beginning of the rehabilitation program and at 6 months, with a mid-term evaluation at 3 months. We included 28 MFS patients between 7 and 20 years (mean 12.8 ± 3.69 years), of which 11 were females, with a mild aortic dilatation for 50% (mean z-score +2.4), no major valvopathy, no cardiac impairment and a history of pneumothorax for 3 of them; most where under preventive beta-blocker treatment (93%). After a 6-month rehabilitation program no progression in aortic diameters was found. Significant improvement in first ventilatory-threshold was achieved (+15.8% of expected value; P < 0.05), alongside an increase in maximal sustained workload with a mean of +24.5 Watts (17.37–31.63; P < 0.05) associated to a significant increase in VO 2 (+131.58 mL.min−1; 30.17–232.99; P < 0.05), whereas maximal heart rate at effort was reduced by 29.95 bpm (16.17–43.73; P < 0.05). Muscular strength gain was shown both by dominant hand-grip (mean +4.3 kg; 2.45–5.2; P < 0.05) and dominant leg strength (+67.33 Nm; 25.08–109.59; P < 0.05). Overall, self and proxy-reported QoL of participants improved (Fig. 1). Young patients with MFS can safely benefit for a home-based rehabilitation program personalised according to their baseline capacities, improving both their overall fitness, muscular strength and cardiovascular health; with a favourable impact in their global QoL. [ABSTRACT FROM AUTHOR]

Marfan syndrome (MFS) is a rare genetic disease leading to a multisystem damage related to connective tissue fragility.Chronic fatigue and decreased physical endurance are almost constant complaints of patients with MFS, whose muscular mass is reduced from childhood, which could explain the bone mass deficit observed in this population. We hypothesize that a personalized rehabilitation program will improve general fitness and quality of life of these patients. Self-controlled study with a 6-month home-based cyclo-ergometer and muscular strengthening personalised rehabilitation program based on first ventilatory-threshold. Baseline evaluation was performed 3 months prior to the start of the rehabilitation program (control), then at the beginning of the program and at 6 months, with a mid-term evaluation at 3 months. We included 28 MFS patients between 7 and 20 years (mean 12.8 ± 3.69 years, 39% females), with a mild aortic dilatation for 50% (mean z-score +2,4), no major valvopathy, no cardiac impairment and a history of pneumothorax for 3 of them; most where under preventive beta-blocker treatment (93%). After a 6-month rehabilitation program no progression in aortic diameters, heart-rate or arterial pressure was found. Significant improvement in first ventilatory-threshold was achieved (mean +4,54 mL.min-1.kg-1; P = 0.035) (Figure 1), alongside an increase in maximal sustained workload with a mean +24.5 Watts (P < 0.001) associated to a small but significant increase in VO2 (+131.58 ml.min-1; P = 0.016). Muscular strength gain was shown both by dominant hand-grip (mean +4.3 kg; P < 0.001) and dominant leg strength (+67.33 Nm; P = 0.005). Overall, QoL of participants improved according to self-reported and proxy-reported total score, physical health and social function. Young patients with Marfan or associated syndromes can safely benefit for a home-based personalised rehabilitation program, improving both their overall fitness, muscular strength and cardiovascular health; with a favourable impact in their QoL. [ABSTRACT FROM AUTHOR]

Nutritional vitamin D supplements are often used in general pediatrics. Here, the aim is to address vitamin D supplementation and calcium nutritional intakes in newborns, infants, children, and adolescents to prevent vitamin D deficiency and rickets in general populations. We formulated clinical questions relating to the following categories: the Patient (or Population) to whom the recommendation will apply; the Intervention being considered; the Comparison (which may be "no action," placebo, or an alternative intervention); and the Outcomes affected by the intervention (PICO). These PICO elements were arranged into the questions to be addressed in the literature searches. Each PICO question then formed the basis for a statement. The population covered consisted of children aged between 0 and 18 years and premature babies hospitalized in neonatology. Two groups were assembled: a core working group and a voting panel from different scientific pediatric committees from the French Society of Pediatrics and national scientific societies. We present here 35 clinical practice points (CPPs) for the use of native vitamin D therapy (ergocalciferol, vitamin D 2 and cholecalciferol, vitamin D 3) and calcium nutritional intakes in general pediatric populations. This consensus document was developed to provide guidance to health care professionals on the use of nutritional vitamin D and dietary modalities to achieve the recommended calcium intakes in general pediatric populations. These CPPs will be revised periodically. Research recommendations to study key vitamin D outcome measures in children are also suggested. [ABSTRACT FROM AUTHOR]

The current French national guidelines were elaborated by a working group consisting of experts in the field of pediatric endocrinology, rheumatology, hepatogastroenterology, nephrology, and pneumology. A systematic search was undertaken of the literature published between 2008 and 2018 and indexed in PubMed. The recommendations developed were then validated by an external evaluation group comprising representatives from the various highly specialized fields in pediatrics, representatives of the societies and groups supporting the development of the guidelines, and representatives of different healthcare professions. The objective of these guidelines was to detail the current optimal management of children at risk of secondary bone fragility. [ABSTRACT FROM AUTHOR]

Résumé Le syndrome de Loeys-Dietz est une forme rare de maladie du tissu conjonctif dont les symptômes sont apparentés au syndrome de Marfan mais dont le phénotype peut être plus fruste. Mise en évidence récemment, cette affection demeure méconnue, alors que ses conséquences peuvent être dramatiques, notamment en raison des atteintes cardiovasculaires. Nous rapportons le cas d’une enfant de 4 ans suivie pour une luxation congénitale de la hanche chez laquelle un examen systématique a mis en évidence une hyper-élasticité cutanée et une luette bifide, faisant évoquer une pathologie du tissu conjonctif. Les signes squelettiques étaient frustes, la taille étant normale pour l’âge. Il n’y avait pas d’antécédents familiaux, cardiologiques ou non, en faveur d’une pathologie des tissus conjonctifs. Les explorations cardiologiques ont permis de découvrir un anévrysme de l’aorte ascendante au niveau du sinus de Valsalva (26 mm, Z-score + 4,24). L’analyse génétique a mis en évidence une mutation du gène transforming growth factor-beta receptor type II ( TGFβR2 ), posant le diagnostic de syndrome de Loeys-Dietz. Des atteintes squelettiques associées à une bifidité de la luette ou un hypertélorisme et un anévrysme de l’aorte ascendante doivent orienter l’enquête génétique vers la recherche d’une vasculopathie par anomalie de la voie du TGFβ telle que le syndrome de Loeys-Dietz. Summary Loeys-Dietz syndrome is a rare form of connective tissue disorder, whose clinical features can resemble those of Marfan syndrome, but with a more unpolished appearance. Recently brought out, this pathology remains little known; however, its consequences may be dramatic. We report on the case of a 4-year-old girl followed for a congenital hip dislocation, in which a systematic exam found increased cutaneous elasticity and a bifid uvula, suggesting a connective tissue disorder. Symptoms were unpolished, as the child's height was normal, without any positive cardiac, rheumatological, or ophthalmological family history. Cardiovascular tests found a thoracic aortic aneurysm at the Valsalva sinus (26 mm, Z-score = +4.24). A genetic investigation found a TGFβR2 gene mutation, leading to the diagnosis of Loeys-Dietz syndrome type 2. Skeletal damage associated with bifid uvula and/or hypertelorism and an aneurysm of the ascending aorta should guide the genetic investigation to the search for TGF-β vasculopathy such as Loeys-Dietz syndrome. [ABSTRACT FROM AUTHOR]

Early diagnosis of Marfan syndrome (MFS) leads us to a comprehensive approach to the multisystem damage related to connective tissue fragility. Impairment in exercise capacity has a great impact on quality of life (QoL) and rehabilitation programs need to address his ultimate causes. We have analysed fitness capacities of patients from a young age until early adulthood, and analysed the causes of limitation. This study included 28 Marfan or associated syndrome patients between 7 and 20 years (average 12.6 years), with mild aortic dilatation for 50% (mean z -score +2,4), no major valvulopathy, no cardiac impairment and history of pneumothorax for 3 of them; most where under preventive betablocker treatment (93%). All of them performed a cardiopulmonary exercise test (CPET) on step incremental cycloergometer. All but one patient reached maximum effort. Results confirm the disease's significant impact on the exercise capacity from a young age. The VO2max values were severely impaired in this population, on average reaching 63.4% of the expected values (mean peak of 104 Watts, 72% of expected work), with a limitation occurring in 71% and resulting from peripheral muscle deconditioning beside chronotropic limitation from betablockers (mean heart rate at peak of 163 bpm, 80.7% of the theoretical maximum). No intrinsic cardiac or pulmonary limitation was observed whereas dyspnoea was a major limiting factor in our patients, over muscular fatigue (dotted 6.5/10 vs. 5.8/10, respectively). These results were correlated to QoL when compared to a control population. The impact of the Marfan syndrome's multisystemic damage and physical impairment through muscular deconditioning is evident from a young age and should not be neglected. Namely, the care provided to patients should include adapted physical activity programs from a young age. [ABSTRACT FROM AUTHOR]

Abstract: Delayed puberty is defined in girls by the absence of breast development beyond 13 years old and in boys by the absence of testicular enlargement (<4ml) beyond 14 years old. Simple investigations lead to the diagnosis of central or peripheral hypogonadism and constitutional delay of puberty. In girls, delayed puberty is rare and often organic, and then Turner syndrome should be systematically suspected. In boys, delayed puberty is often constitutional and functional. Treatment is etiologic when possible, hormonal replacement therapy (oestrogen in girls and testosterone in boys) and psychological management. [Copyright &y& Elsevier]

Summary: Growth hormone (GH), secreted by the anterior pituitary into the circulation, binds to membrane receptors in target tissues to stimulate body growth; most of its effects is mediated by the insulin-like growth factor 1 (IGF-1). In addition to promoting growth, GH has important metabolic actions. The syndrome of GH insensitivity (GHI) was first identified in 1966 by Laron et al. in three children with clinical phenotype characteristic of growth hormone deficiency but associated with elevated serum concentration of GH. Direct evidence of a GH receptor (GHR) abnormality was provided in 1989. More recently, molecular abnormalities in the postreceptor signalling mechanism were found. Mutations of signal transducer and activator of transcription 5b (Stat5b) were reported in patients with growth retardation and primary immunodeficiency. Mutations of the tyrosin phosphatase Shp2 were identified in patients affected by Noonan syndrome characterized by short stature, cardiopathy and increased risk of leukaemia. The unmasking of the molecular bases for these defects will contribute greatly to our future understanding of both normal and aberrant growth. Moreover, this knowledge should bring insight on cancerogenesis or immunodeficiency caused by cytokines resistance. [Copyright &y& Elsevier]

Summary: Eighty-five percent of children born with IUGR have spontaneous catch-up growth in the first 2 years of life, however, about 10 to 15% do not catch up. Numerous therapeutic trials have demonstrated the efficacy of GH treatment in these children. However, the duration of this treatment is still discussed. Objective: The aim of this study was to describe the evolution of growth during and after the end of treatment. Population and methods: This study followed 33children in our unit, treated with growth hormone under the French indication (3 years of treatment followed by 1 year off treatment) and with a mean follow-up of 3 years after cessation. Results: During the 3 years of therapy, we confirmed an increase in growth velocity that resulted in a mean height above −2 standard deviation score (SDS) in 25children at 3 years (mean height of 1.4SDS). Among the 25children who achieved a height above −2SDS at three years and therefore stopped treatment, 15 resumed GH due to a secondary catch-down. Among children who didn’t catch-up at 3 years, the continuation of GH treatment didn’t seem to improve the growth. [Copyright &y& Elsevier]

Marfan and Loeys-Dietz syndromes are connective tissue disorders characterized by high clinical variability. The major morbidity and mortality in both syndromes relate to the dilatation of the aorta predisposing to aortic tear. We investigated the putative relationship between the genotype, aortic growth speed and the occurrence of severe cardio vascular events (prophylactic surgery of the aortic root, aortic dissection or related death). We have performed a retrospective study of 102 patients with pathogenic variants in FBN1, TGFβR1 and R2 and SMAD3 genes followed at a Marfan reference center in France. The average age at the start of the study was 13.8 years and data were collected over 5 years. The FBN1 variants were classified as haploinsufficient (HI) or dominant negative (DN). Aortic diameters and aortic dilatation at the level of the Valsalva sinuses were assessed by echocardiography. No overall aortic growth difference was found between Marfan and Loeys-Dietz syndrome (1,14 vs. 1,11 mm/year, P = 0,74), neither between HI and DN groups (1,12 vs. 1,01 mm/year, P = 0,36). However, patients with a SMAD 3 mutation seem to have lower aortic growth than those in the TGFβ group (0,91 vs. 1,34 mm/year, P = 0,36). No difference concerning Valsalva sinus Z score evolution was found between these groups. We didn't find any differences concerning the occurrence of cardio vascular events between Marfan and Loeys Dietz syndrome and their genetics subgroups. Aortic growth in men was significantly faster than in women (1,23 vs. 0,91 mm/year, P = 0,005). Marfan syndrome and Loeys-Dietz, as well as their genetics subgroups should be monitored similarly for the development of aortic root aneurysm. Like other phenotypic characteristics of these syndromes, the cardio vascular manifestations present a high variability among patients and a correlation genotype/phenotype is not informative for patient care. A possible exception is the TGFβ group, which may grow faster. [ABSTRACT FROM AUTHOR]

Pathogenic variants in SMAD3 (type 3 LDS, Marfan-like connective tissue disorder) cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Generally, these aggressive vascular damages are associated with multisystemic signs including skeletal abnormalities and premature osteoarthritis. Variable expressivity and incomplete penetrance are commonly associated. Aortic status, events, and clinical features were abstracted through retrospective review of medical records 20 new patients (28.8 years-old (6–60)) from 8 families from our Reference Centre. After a complete review of the literature, we collected a total of 49 unique variants of different nature (missense, truncating and splicing variants) from 152 individuals of 58 unrelated families. The aim of this study was to look for genotype-phenotype correlations between the mutations of this gene and the severity of the phenotype. Aortic aneurysm and/or dissection are the main vascular findings, affecting respectively 57% and 32% of all type 3 LDS patients described. In our cohort of patients, half presents an aortic dilatation (10/20), 10% an aortic dissection. Three of our patients displays an aortic dilatation during their childhood (at 8 and 7 years old and a surgery for an aortic dilation at 10 years old). Aneurysms and dissections can also be seen in other arteries in 27% (35/138) and particularly intracranial aneurysms found in 20% of patients (21/103), like in two of our patients, one presented an iliac artery dissection. Arterial tortuosity is also frequent, particularly in carotids, representing about a third of the patients (36/117 = 31%), 2 of our 8 patients. SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. We confirmed that there is no correlation between the mutation type and the phenotype severity. Aneurysms-Osteoarthritis syndrome (AOS), genotype-phenotype correlation, heritable thoracic aortic aneurysms and dissections (hTAAD), Loeys-Dietz syndrome, SMAD3, Marfan-like connective tissue disorder, TGFβ pathway. [ABSTRACT FROM AUTHOR]

Pathogenic variants in SMAD3 (type 3 LDS, Marfan-like connective tissue disorder) cause thoracic aortic aneurysms and dissections, along with aneurysms and rupture of other arteries. Generally, these aggressive vascular damages are associated with multisystemic signs including skeletal abnormalities and premature osteoarthritis. Variable expressivity and incomplete penetrance are commonly associated. Aortic status, events, and clinical features were abstracted through retrospective review of medical records 20 new patients (28.8 years-old (6–60)) from 8 families from our Reference Centre. After a complete review of the literature, we collected a total of 49 unique variants of different nature (missense, truncating and splicing variants) from 152 individuals of 58 unrelated families. The aim of this study was to look for genotype-phenotype correlations between the mutations of this gene and the severity of the phenotype. Aortic aneurysm and/or dissection are the main vascular findings, affecting respectively 57% and 32% of all type 3 LDS patients described. In our cohort of patients, half presents an aortic dilatation (10/20), 10% an aortic dissection. Three of our patients displays an aortic dilatation during their childhood (at 8 and 7-years-old and a surgery for an aortic dilation at 10-years-old). Aneurysms and dissections can also be seen in other arteries in 27% (35/138) and particularly intracranial aneurysms found in 20% of patients (21/103), like in two of our patients, one presented an iliac artery dissection. Arterial tortuosity is also frequent, particularly in carotids, representing about a third of the patients (36/117 = 31%), 2 of our 8 patients. SMAD3 pathogenic variants cause thoracic aortic aneurysms and dissections in the majority of individuals with variable age of onset and reduced penetrance. We confirmed that there is no correlation between the mutation type and the phenotype severity. [ABSTRACT FROM AUTHOR]

Résumé: La biologie du métabolisme minéral osseux a connu ces dernières années des avancées importantes. Plusieurs syndromes pédiatriques ont été précisés sur le plan moléculaire. Il existe une intrication étroite entre les composantes endocriniennes de la régulation métabolique et la trophicité du tissu osseux. L’accent est mis désormais sur l’impact anabolique sur l’os des traitements à visée osseuse, tels les biphosphonates, la parathormone (PTH) ou l’hormone de croissance. Ces éléments sont importants pour le devenir de l’os à l’âge adulte. Nous analysons ici les composantes essentielles de la régulation du métabolisme osseux minéral au vu des données récentes de la biologie, telles que la signalisation liée au système PTH/PTHrP (PTH-related peptide), le rôle du FGF23 (Fibroblast growth factor 23) dans les hypophosphatémies et la régulation du métabolisme de la vitamine D par la 1α-hydroxylase. Ces éléments de régulation sont intriqués dans plusieurs pathologies génétiques et dans le syndrome de Mc Cune-Albright. L’interaction entre facteurs métaboliques et endocriniens sera analysée en évaluant son impact sur la sécrétion de PTH et sur l’ostéogenèse. [Copyright &y& Elsevier]

Résumé Nous rapportons le cas d’une hernie diaphragmatique découverte chez un nourrisson atteint du syndrome de Marfan, diagnostiquée après la réalisation d’une radiographie et d’une échographie cardiaque devant l’association d’une altération de l’état général, d’une stagnation pondérale et de signes de lutte respiratoire. Un rappel est fait sur l’association classique entre syndrome de Marfan et hernie diaphragmatique, ainsi que sur la démarche diagnostique. Summary The authors report on a case of diaphragmatic hernia occurring in a 3-month-old child affected by Marfan syndrome. Diagnosis was made on a chest X-ray and cardiac ultrasounds, performed because of the association of poor general condition, failure to thrive, and signs of respiratory distress. As a reminder, we emphasize the association between Marfan disease and diaphragmatic hernias as well as the diagnostic approach to reach an appropriate diagnosis. [ABSTRACT FROM AUTHOR]

Résumé Le rachitisme carentiel reste un problème de santé publique majeur dans de nombreuses parties du monde. Alors qu’il avait quasiment disparu dans les pays industrialisés suite à la supplémentation systématique en vitamine D chez l’enfant, plusieurs études récentes (notamment danoises et anglaises) suggèrent une augmentation de son incidence, notamment chez le nourrisson. À côté des manifestations osseuses classiques, le rachitisme peut se manifester par des complications neurologiques et cardiaques qui peuvent mettre en jeu le pronostic vital dans les formes les plus sévères ; un dépistage et une prise en charge précoces sont donc importants. Nous rapportons le cas d’un nourrisson de 2 ans qui présentait un rachitisme carentiel sévère associé à des convulsions et à une cardiomyopathie ayant permis de dépister un rachitisme chez les autres enfants de la fratrie. Ces observations soulignent l’importance d’une vigilance maintenue sur cette pathologie, notamment dans les populations particulièrement exposées du fait de facteurs socioculturels. Summary Nutritional rickets remains a significant public health issue for children worldwide. Although it has almost disappeared in industrialized countries following routine vitamin D supplementation, recent evidence suggests an increasing incidence, especially in young children. In addition to the classical clinical consequences on bone and the growth plate, rickets may also be associated with life-threatening neurological and cardiac complications in the most severe forms. Consequently, early screening and treatment are required. Here, we report the case of a 2-year-old child who presented with severe nutritional rickets associated with seizure and cardiomyopathy. Family screening revealed rickets in all the siblings. This case report emphasizes the importance of being aware of this disease, notably in population with sociocultural risk factors. [ABSTRACT FROM AUTHOR]

Statural growth is underpinned by development of the growth plate during the process of endochondral ossification, which is strongly regulated by numerous local factors (intracellular, paracrine and extracellular matrix factors) and systemic factors (nutrition, hormones, proinflammatory cytokines and extracellular fluids). This explains why growth retardation can be associated with numerous pathologies, particularly genetic syndromes, hormonal or inflammatory conditions, or gastrointestinal disorders having a nutritional impact. However, in most cases (80%), no specific aetiology is found after clinical investigation and conventional additional tests have been carried out. In such cases, "idiopathic" short stature is diagnosed, which includes patients presenting with constitutional delay of growth and development and familial short stature, but also patients with very subtle constitutional skeletal dysplasia which are not easily identifiable. In recent years, new methods of genetic investigation (e.g. gene panels, exome or genome sequencing) have made it possible to identify many genetic variants associated with apparently isolated short stature. Indeed, it is still difficult to estimate the proportion of patients presenting with idiopathic short stature for which a molecular diagnosis of monogenic conditions could be made. This estimate varies hugely depending on the thoroughness of the clinical, laboratory and radiological assessments performed prior to molecular analysis, since retrospective analysis of positive cases usually reveals subtle signs of underlying syndromes or rare skeletal disorders. Molecular diagnosis in children is important to be able to offer genetic counselling and to organise patient management. Moreover, improved understanding of the molecular basis of these cases of short stature opens up numerous possibilities for more specific treatments targeting the growth plate. © 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved. [ABSTRACT FROM AUTHOR]

Objectifs Décrire la présentation clinique de la maladie de Gorham chez un nourrisson, sa prise en charge et son évolution au niveau oncologique et osseux. Sujet Un nourrisson de 6 mois est admis en réanimation pour une hémorragie pulmonaire massive avec bicytopénie périphérique. Résultats Les différents examens d’imagerie (TDM, IRM et radiographies os) retrouvent une atteinte alvéolaire à contenu hématique diffuse associée à des lacunes osseuses multiples intéressant le rachis, les os long, le crâne et le bassin ; il n’y a pas de malformation vasculaire. La biopsie osseuse retrouve une lésion vasculaire endothéliale intra-osseuse agressive compatible avec une maladie de Gorham. Un traitement est initié par Interféron alpha associé à des cures de biphosphonates, tout d’abord pamidronate puis zoledronate. Après 9 mois de traitement, il existe une disparition des signes cliniques (absence d’hémoptysie), une stabilisation des plaquettes, une diminution des lésions pulmonaires et osseuses, et une amélioration des marqueurs biologiques osseux (ostéocalcine, PAL, crosslaps). Conclusion Il s’agit du premier cas décrit dans la littérature de maladie de Gorham à révélation précoce d’évolution actuellement favorable sous biphosphonates et Interféron alpha sans effets indésirables. [ABSTRACT FROM AUTHOR]