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Wilson's disease (WD) is usually diagnosed in children and young adults; limited data exist on late-onset forms.The aim was to characterize the clinical and paraclinical presentations, therapeutic management, and outcomes in patients with late-onset WD.Patients diagnosed with WD after age 40 years were identified from the French Wilson's Disease Registry (FWDR). Clinical, laboratory, and imaging findings and treatment were reported at diagnosis and last follow-up.Forty-five patients were identified (median age: 49, range: 40-64) and placed in three groups according to their clinical presentation: neurological (n = 20, median diagnostic delay: 20 months), hepatic (n = 13, diagnostic delay: 12 months), and family screening (n = 12), all confirmed genetically. Six neurological patients had an atypical presentation (1 torticollis, 2 writer's cramps, 2 functional movement disorders, and 1 isolated dysarthria), without T2/fluid-attenuated inversion recovery brain magnetic resonance imaging (MRI) hyperintensities; 5 of 6 had no Kayser-Fleischer ring (KFR); 5 of 6 had liver involvement. In the neurological group, 84% of patients improved clinically, and 1 developed copper deficiency. In the hepatic group, 77% had cirrhosis; 6 patients required liver transplantation. In the screened group, 43% had mild liver involvement; 3 were not treated and remained stable; 24-h urinary copper excretion was normal in 33% of patients at diagnosis.In the FWDR, late-onset forms of WD affect 8% of patients, mostly with neurological presentations. Thirty percent of the neurological forms were atypical (isolated long-lasting symptoms, inconspicuous brain MRI, no KFR). With personalized treatment, prognosis was good. This study emphasized that WD should be suspected at any age and even in cases of atypical presentation. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Background and ObjectivesKCNH5encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novoKCNH5variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies forKCNH5variants using targeted or exome sequencing. Additional individuals withKCNH5variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included 3 previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including 9 with a recurrent de novo missense variant p.Arg327His, 4 with a recurrent missense variant p.Arg333His, and 4 additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using the American College of Medical Genetics and Genomics criteria. All individuals presented with epilepsy with a median seizure onset at 6 months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalized epilepsy and normal intellect, whereas the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore domain were more severely affected, with a neonatal-onset movement disorder, early-infantile DEE, profound disability, and childhood death.DiscussionWe describe a cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage-sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establishKCNH5as implicated in a spectrum of neurodevelopmental disorders and epilepsy.

Objectives To investigate whether the lactate dehydrogenase D (LDHD) gene deficiency causes juvenile-onset gout. Methods We used whole-exome sequencing for two families and a targeted gene-sequencing panel for an isolated patient. d-lactate dosages were analysed using ELISA. Results We demonstrated linkage of juvenile-onset gout to homozygous carriage of three rare distinct LDHD variants in three different ethnicities. In a Melanesian family, the variant was (NM_153486.3: c.206C>T; rs1035398551) and, as compared with non-homozygotes, homozygotes had higher hyperuricaemia (P = 0.02), lower fractional clearance of urate (P = 0.002), and higher levels of d-lactate in blood (P = 0.04) and urine (P = 0.06). In a second, Vietnamese, family, very severe juvenile-onset gout was linked to homozygote carriage of an undescribed LDHD variant (NM_153486.3: c.1363dupG) leading to a frameshift followed by a stop codon, p.(AlaGly432fsTer58). Finally, a Moroccan man, with early-onset and high d-lactaturia, whose family was unavailable for testing, was homozygous for another rare LDHD variant [NM_153486.3: c.752C>T, p.(Thr251Met)]. Conclusion Rare, damaging LDHD variants can cause autosomal recessive early-onset gout, the diagnosis of which can be suspected by measuring high d-lactate levels in the blood and/or urine.

Monogenic early onset osteoporosis (EOOP) is a rare disease defined by low bone mineral density (BMD) that results in increased risk of fracture in children and young adults. Although several causative genes have been identified, some of the EOOP causation remains unresolved. Whole-exome sequencing revealed a de novo heterozygous loss-of-function mutation in Wnt family member 11 (WNT11) (NM_004626.2:c.677_678dup p.Leu227Glyfs*22) in a 4-year-old boy with low BMD and fractures. We identified two heterozygous WNT11 missense variants (NM_004626.2:c.217G > A p.Ala73Thr) and (NM_004626.2:c.865G > A p.Val289Met) in a 51-year-old woman and in a 61-year-old woman, respectively, both with bone fragility. U2OS cells with heterozygous WNT11 mutation (NM_004626.2:c.690_721delfs*40) generated by CRISPR-Cas9 showed reduced cell proliferation (30%) and osteoblast differentiation (80%) as compared with wild-type U2OS cells. The expression of genes in the Wnt canonical and non-canonical pathways was inhibited in these mutant cells, but recombinant WNT11 treatment rescued the expression of Wnt pathway target genes. Furthermore, the expression of RSPO2, a WNT11 target involved in bone cell differentiation, and its receptor leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), was decreased in WNT11 mutant cells. Treatment with WNT5A and WNT11 recombinant proteins reversed LGR5 expression, but Wnt family member 3A (WNT3A) recombinant protein treatment had no effect on LGR5 expression in mutant cells. Moreover, treatment with recombinant RSPO2 but not WNT11 or WNT3A activated the canonical pathway in mutant cells. In conclusion, we have identified WNT11 as a new gene responsible for EOOP, with loss-of-function variant inhibiting bone formation via Wnt canonical and non-canonical pathways. WNT11 may activate Wnt signaling by inducing the RSPO2–LGR5 complex via the non-canonical Wnt pathway.

ObjectiveKCNH5 encodes the voltage-gated potassium channel EAG2/Kv10.2. We aimed to delineate the neurodevelopmental and epilepsy phenotypic spectrum associated with de novo KCNH5 variants.MethodsWe screened 893 individuals with developmental and epileptic encephalopathies (DEEs) for KCNH5 variants using targeted or exome sequencing. Additional individuals with KCNH5 variants were identified through an international collaboration. Clinical history, EEG, and imaging data were analyzed; seizure types and epilepsy syndromes were classified. We included three previously published individuals including additional phenotypic details.ResultsWe report a cohort of 17 patients, including nine with a recurrent de novo missense variant p.Arg327His, four with a recurrent missense variant p.Arg333His, and four additional novel missense variants. All variants were located in or near the functionally critical voltage-sensing or pore domains, absent in the general population, and classified as pathogenic or likely pathogenic using American College of Medical Genetics and Genomics (ACMG) criteria. All individuals presented with epilepsy with a median seizure onset at six months. They had a wide range of seizure types, including focal and generalized seizures. Cognitive outcomes ranged from normal intellect to profound impairment. Individuals with the recurrent p.Arg333His variant had a self-limited drug-responsive focal or generalised epilepsy and normal intellect, while the recurrent p.Arg327His variant was associated with infantile-onset DEE. Two individuals with variants in the pore-domain were more severely affected, with neonatal-onset DEE, profound disability, and childhood death.ConclusionsWe report the first cohort of 17 individuals with pathogenic or likely pathogenic missense variants in the voltage sensing and pore domains of Kv10.2, including 14 previously unreported individuals. We present evidence for a putative emerging genotype-phenotype correlation with a spectrum of epilepsy and cognitive outcomes. Overall, we expand the role of EAG proteins in human disease and establish KCNH5 as implicated in a spectrum of neurodevelopmental disorders (NDDs) and epilepsy.

Primary hypertrophic osteoarthropathy (PHO), or pachydermoperiostosis, is characterized by a clinical association including digital clubbing, periostosis and pachydermia. SLCO2A1 and HPGD genes are both responsible for PHO. The pathology is classically defined as an autosomal recessive disorder with clinical variability ranging from a mild to more severe phenotype. However, the hypothesis for an autosomal dominant form suggested for a long time was only demonstrated for the first time in 2021 for SLCO2A1. We aimed to detect a second pathogenic variant by a deep sequencing of the entire SLCO2A1 and HPGD genes, associated with functional transcription analysis in PHO patients harboring only one heterozygous variant. Among 10 PHO patients, 4 presented a single pathogenic or probably pathogenic novel variant in SLCO2A1 in heterozygous status (NM_005630.3: c.234+1G A, c.1523_1524delCT, c.1625G A and c.31delC), and the others carried homozygous pathogenic variants. For heterozygous forms, we found no additional pathogenic variant in HPGD or SLCO2A1. PHO can be a dominant form with age at disease onset later than that for the recessive form. This dominant form is not exceptional in young adults. In conclusion, both modes of inheritance of PHO explain the clinical variability and the difference in age at disease onset. Molecular analysis is especially required in the incomplete form to distinguish it from secondary hypertrophic osteoarthropathy.

Coronary artery calcifications (CAC) are frequently observed in patients referred for coronary CT angiography (CTA). Calcification volume (in mm3) can accurately be assessed during catheterization by optical coherence tomography (OCT). The aim of the present study was to investigate the accuracy of CTA-derived assessment of calcification volume as compared with OCT. 66 calcified plaques (32 vessels) from 31 patients undergoing OCT-guided PCI with coronary CT acquired as a standard of care were included. Coronary CT and OCT images were matched using fiduciary points. Calcified plaques were reconstructed in three dimensions to calculate calcium volume. A Passing-Bablok regression analysis and the Bland-Altman method were used to assess the agreement between imaging modalities. Twenty-seven left anterior descending arteries and 5 right coronary arteries were analyzed. Median calcium volume by CTA and OCT were 18.23 mm3 [IQR 8.09, 36.48] and 10.03 mm3 [IQR 3.6, 22.88] respectively; the Passing-Bablok analysis showed a proportional without a systematic difference (Coefficient A 0.08, 95% CI - 1.37 to 1.21, Coefficient B 1.61, 95% CI 1.45 to 1.84) and the mean difference was 9.69 mm3 (LOA - 10.2 to 29.6 mm3). No differences were observed for minimal lumen area (Coefficient A 0.07, 95% CI - 0.46 to 0.15, Coefficient B 0.85, 95% CI 0.64 to 1.2). CTA volumetric calcium evaluation overestimates calcium volume by 60% compared to OCT. This may allow for an appropriate interpretation of calcific burden in the non-invasive setting. Even in presence of calcific plaques, a good agreement in the MLA assessment was found. Coronary CT may emerge as a tool to quantify calcium burden for invasive procedural planning.

International audience; Purpose: Early and reliable prognostication after cardiac arrest (CA) remains crucial. We hypothesized that protein-S100B (PS100B) could predict more accurately outcome in the early phase of CA compared with other current biomarkers.Methods: This prospective single-center study included 330 adult comatose non-traumatic successfully resuscitated CA patients, treated with targeted temperature management but not extra-corporeal life support. Lactate, pH, creatinine, NSE, and PS100B were sampled in ICU early after return of spontaneous circulation (ROSC) corresponding to admission (Adm). Serial measurements were also performed at H24 and H48. PS100B was the sole biomarker blinded to physicians.Measurements and main results: The median delay between ROSC and first PS100B sampling was 220 min. At admission, all biomarkers were significantly associated with good outcome (CPC1-2; 109 patients) at 3-month follow-up (P ≤ 0.001, except for NSE: P = 0.03). PS100B-Adm showed the best AUC of ROC curves for outcome prediction at 3-month (AUC 0.83 [95%-CI: 0.78-0.88]), compared with other biomarkers (P < 0.0001), while AUC for lactate-Adm was higher than for NSE-Adm. AUC for PS100B-H24 was significantly higher than for other biomarkers except NSE-H24 (P ≤ 0.0001), while AUC for NSE-H24 was higher than for lactate-H24 and pH-H24. AUCs for PS100-H48 and NSE-H48 were significantly higher than for all other biomarkers (P < 0.001). Compared to patients with decreased PS100B values over time, an increasing PS100B value between admission and H24 was significantly associated with poor outcome at 3 months (P = 0.001). No-flow, initial non-shockable rhythm, PS100B-Adm, lactate-Adm, pH-Adm, clinical seizures, and absence of therapeutic hypothermia were independent predictors associated with poor outcome at 3-month in multivariate analysis. Net-Reclassification-Index was 70%, 64%, and 81% when PS100B-Adm was added to the clinical model, to clinical model with NSE-Adm, and to clinical model with standard biological parameters, respectively.Conclusions: Early PS100B compared with other biomarkers was independently correlated with outcome after CA, with an interesting added value.

Craniodiaphyseal dysplasia (CDD) is an ultra-rare and severe sclerosing bone dysplasia, usually presenting in early childhood with progressive sclerosis of the cranial and facial bones. Heterozygous variants in the SOST gene have been reported in two unrelated CDD patients. We now report on two subjects from a large consanguineous family with mild phenotypic features of CDD. Physical examination revealed facial dysmorphism, short stature and a lean body habitus. Radiographs showed severe hyperostosis of the calvarium, skull base and mandibula, broadened claviculae and ribs, scoliosis, and diaphyseal expansion of the long bones. One of the two subjects had a history of recurrent fractures. Serum analysis in the proband revealed very high levels of bone formation (P1NP, osteocalcin) and resorption markers (CTX-1, TRAcP 5b), suggesting a high bone turnover. Exome sequencing led to the identification of a homozygous missense variant (c.913T>C, p.(Tyr305His)) in SP7, encoding the Osterix transcription factor. The variant is located in the first zinc-finger domain, a highly conserved region responsible for DNA-binding. Luciferase reporter assays were performed to investigate the DNA-binding capacity of mutant Osterix to AT-rich sequences, as these motifs mediate the transcription of genes in osteoblasts. This analysis showed a 90 % loss in binding capacity of mutant Osterix. Based on our data, we hypothesize that our variant may have neomorphic effects resulting in the SP7-related autosomal recessive CDD phenotype. Further studies are required to dissect the precise mechanisms on how bi-allelic variants in SP7 can cause a sclerosing bone dysplasia.

Faciocraniosynostoses (FCS) are malformations affecting the development of the bones of the skull and face, due to the premature closure of one or more craniofacial sutures, mostly secondary to activatingWe retrospectively collected height and weight data from a cohort of 70 patients. Included patients were admitted forWe showed thatPatients with

International audience; Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.

The osteopetroses and related sclerosing bone dysplasias can have a broad range of manifestations. Especially in the milder forms, sandwich vertebrae are an easily recognizable and reliable radiological hallmark. We report on four patients from three families presenting with sandwich vertebrae and platyspondyly. The long bone phenotypes were discordant with one patient showing modeling defects and patchy osteosclerosis, while the second displayed only metaphyseal sclerotic bands, and the third and fourth had extreme metaphyseal flaring with uniform osteosclerosis. Two of the four patients had experienced pathological fractures, two had developmental delay, but none showed cranial nerve damage, hepatosplenomegaly, or bone marrow failure. According to these clinical features the diagnoses ranged between intermediate autosomal recessive osteopetrosis and dysosteosclerosis. After exclusion of mutations in CLCN7 we performed gene panel and exome sequencing. Two novel mutations in SLC29A3 were found in the first two patients. In the third family a TCIRG1 C-terminal frameshift mutation in combination with a mutation at position +4 in intron 2 were detected. Our study adds two cases to the small group of individuals with SLC29A3 mutations diagnosed with dysosteosclerosis, and expands the phenotypic variability. The finding that intermediate autosomal recessive osteopetrosis due to TCIRG1 splice site mutations can also present with platyspondyly further increases the molecular heterogeneity of dysosteosclerosis-like sclerosing bone dysplasias.

25 years old gentleman was brought to the emergency department after a high-velocity car accident...

Background Early‐onset osteoporosis (EOOP) is defined by low bone mineral density (BMD), which increases the risk of fracture. Although the prevalence of osteoporosis at a young age is unknown, low BMD is highly linked to genetic background. Heterozygous pathogenic variants in low‐density lipoprotein receptor‐related protein 5 (LRP5) are associated with EOOP. This study aimed to investigate the genetic profile in patients with EOOP to better understand the variation in phenotype severity by using a targeted gene sequencing panel associated with bone fragility. Method and Results We used a sequencing panel with 17 genes reported to be related to bone fragility for analysis of 68 patients with EOOP. We found a high positivity rate of EOOP with LRP5 variants (14 patients, 20.6%). The remaining 79.4% of patients with EOOP but without LRP5 variants showed variable disease severity, as observed in patients with at least one variant in this gene. One patient, with multiple fractures and spine L1‐L4 BMD Z‐score −2.9, carried a novel pathogenic homozygous variant, c.2918T>C, p.(Leu973Pro), without any pseudoglioma. In addition to carrying the LRP5 variant, 2 other patients carried a heterozygous variant in Wnt signaling pathway genes: dickkopf WNT signaling pathway inhibitor 1 (DKK1) [NM_012242.4: c.359G>T, p.(Arg120Leu)] and Wnt family member 3A (WNT3A) [NM_033131.3: c.377G>A, p. (Arg126His)]. As compared with single‐variant LRP5 carriers, double‐variant carriers had a significantly lower BMD Z‐score (−4.1 ± 0.8) and higher mean number of fractures (6.0 ± 2.8 vs. 2.2 ± 1.9). Analysis of the family segregation suggests the inheritance of BMD trait. Conclusion Severe forms of EOOP may occur with carriage of 2 pathogenic variants in genes encoding regulators of the Wnt signaling pathway. Two‐variant carriers of Wnt pathway genes had severe EOOP. Moreover, DKK1 and WNT3A genes should be included in next‐generation sequence analyses of bone fragility., Gene association may occur in the same signaling pathway and can generate a severe bone phenotype in early‐onset osteoporosis. Recessive form associated with lipoprotein receptor‐related protein 5 could be responsible for a stronger phenotype. Interestingly this recessive form is not associated with ocular problems as observed in pseudoglioma osteoporosis or vitreoretinopathy. Assessment of genetics based on an next generation sequencing panel should include WNT3A and DKK1.

Serotonin or 5-hydroxytryptamine and its receptors are important in central nervous system, but also in peripheral systems such as bone in which the serotonin plays a significant role. The diversity of action of serotonin results from the multiplicity of its receptors and its capability to signal via a receptor-independent mechanism. Serotonin effects on the skeleton are considered to be mediated via its receptors and serotonin transporter in osteoblasts and osteoclasts. There is also evidence that serotonin can be synthesized by osteoclasts and acts to modulate bone metabolism. Better understanding of the roles of serotonin in bone remodeling is necessary to explain the effects of drugs that disturb serotonin signaling as serotonin-specific reuptake inhibitors. Also, 5-HT2A and 5-HT2B receptor agonists and antagonists can potentially lead to therapeutic approaches to treat bone pathologies.

Introduction In patients with heart failure and preserved ejection fraction (HFpEF), even mild atrial functional mitral regurgitation (AFMR) has been associated with poor outcome. Objective To describe long-term effects of endoscopic mitral valve (MV) repair on outcome in patients with HFpEF and AFMR. Methods The study population consisted of consecutive patients with HFpEF (LVEF ≥50%, H2FPEF score ≥5) and AFMR, who underwent isolated, minimally invasive (endoscopic), MV repair (MVRepair group) (n=131) or remained on standard of care (StanCare group) (n=139). Patients with coronary artery disease or organic MR were excluded. Patients were matched using inverse probability of treatment weighting. Primary objective was all-cause mortality or HFpEF readmissions. Results The median follow up was 5.03 years (IQR 2.6–7.9 years). In the MVRepair group, the perioperative, 30-day, 1- and 5-year mortality was 0, 1% and 12%, respectively. Additional 13 (10%) patients were readmitted for worsening HFpEF, while 2 (1%) individuals underwent redo MV surgery for recurrent MR. MVRepair compared with StanCare showed 21–29% (SE 6–8%) and 19–26% (SE 6–8%) absolute risk reduction of all-cause mortality and HFpEF readmissions, respectively (all p Conclusions Endoscopic MV repair is associated with low perioperative mortality, high long-term efficacy and appears to improve clinical outcome in patients with AFMR and HFpEF. Mortality and readmission for HF Funding Acknowledgement Type of funding source: None

Background Hyperemic absolute coronary blood flow (in mL/min) can be safely and reproducibly measured with intracoronary continuous thermodilution of saline at room temperature at an infusion rate of 20 mL/min. This study aims at assessing the best infusion rate to measure resting flow by thermodilution, i.e. low enough to avoid microvascular dilation but high enough to allow reliable thermodilution tracings Methods and results In 26 coronary arteries (24 patients) with angiographic non-significant stenoses, absolute flow was assessed by continuous saline thermodilution at infusion rates of 10 mL/min and 20 mL/min using a pressure/temperature sensored guide wire, a dedicated infusion catheter and a dedicated software. Average peak velocity (APV) was measured simultaneously using an intracoronary Doppler-wire. In addition, in a subgroup of 10 arteries, absolute flow and APV were also measured during saline infusion at 6 ml/min and 8 ml/min. In 26 coronary arteries there was no significance difference in the Pd/Pa and in the APV at baseline and during the infusion of saline at 10 ml/min (Pd/Pa: 0.94±0.057 vs 0.94±0.059, p=0.82; APV: 22.2±8.40 vs 23.2±8.39 cm/s, p=0.63). In contrast, at an infusion rate of 20 mL/min, we observed a significant decrease in Pd/Pa compared to baseline (0.85±0.089 vs 0.95±0.053 vs, respectively, p Conclusion Absolute resting coronary flow can be measured by intracoronary continuous thermodilution of saline at infusion rate of 8–10 ml/min. Funding Acknowledgement Type of funding source: None

Background Coronary artery calcifications are frequently observed in patients referred for cardiac catheterization. Using OCT, the calcified volume can be determined. CT is a sensitive non-invasive tool to detect coronary artery calcifications and may be useful to guide percutaneous coronary intervention. Purpose The aim of the study was to investigate the accuracy of CT-derived calcium volume with OCT as a reference in patients undergoing PCI. Methods 66 calcified plaques (32 vessels) from 31 patients undergoing OCT-guided PCI with coronary CT angiography acquired as a standard of care were included. Coronary CT angiography and OCT images were matched using fiduciary points. Calcified plaques were reconstructed in three dimensions to calculate calcium volume. A Passing-Bablok regression analysis and the Bland-Altman method were used to assess agreement between imaging modalities. Results 27 left anterior descending arteries and 5 right coronary arteries were analyzed. Median calcium volume by CT angiography and OCT were 18.23 mm 3 [IQR 8.09, 36.48] and 10.03 mm 3 [IQR 3.6, 22.88]. The Passing-Bablok analysis showed a proportional difference without a systematic difference (Coefficient A 0.08, 95% CI: −1.37 to 1.21, Coefficient B 1.61, 95% CI: 1.45 to 1.84); with a mean difference of 9.69 mm3 (LOA −10.2 mm 3 to 29.6 mm 3). No significant differences were observed for MLA: median value for CT 2.84 mm2 [IQR 2.03, 3.74] and for OCT 2.55 mm2 [IQR 1.91, 4.43]. Conclusions Coronary CT angiography volumetric calcium evaluation overestimates calcium volume by 60% compared to OCT. Accounting for CT overestimation may allow for appropriate interpretation of calcific burden in the non-invasive setting. Coronary CT angiography may emerge as a tool to quantify calcium burden for invasive procedural planning. Calcium burden comparison CT vs OCT Funding Acknowledgement Type of funding source: None

Background Hypothetical concept of disproportionate secondary mitral regurgitation (SMR) has been recently introduced to facilitate patient's selection for mitral valve intervention. However, real world data validating this concept are unavailable. Purpose To investigate long-term effects of minimally invasive mitral valve annuloplasty (MVA) in patients with disproportionate (dSMR) versus proportionate SMR. Methods The study population consisted of 44 consecutive patients (age 67±9,5 years; 64% males) on guidelines-directed therapy with advanced heart failure (HF), reduced LV ejection fraction (EF) (32±9,7%) and SMR undergoing isolated mini-invasive MVA. Patients with organic mitral regurgitation or concomitant myocardial revascularization were excluded. To assess SMR disproportionality, the PISA-derived effective regurgitant orifice area (EROA) and regurgitant volume (RV) were compared to the estimated EROA and RV by using Gorlin formula and pooled real world data. Results According to EROA, a total of 20 (46%) and 24 (54%) patients, respectively, had dSMR and proportionate SMR (pSMR). According to RV, a total of 17 (39%) had dSMR and 27 (61%) had pSMR. Patients with dSMR showed significantly lower prevalence of male gender and higher prevalence of diabetes mellitus than patients with pSMR (p Conclusions Minimally invasive MVA is associated with significant reduction of HF readmissions in patients with dSMR versus pSMR while the mortality is similar. This suggests the importance of other parameters, i.e. age and degree of LV remodeling, to guide clinical management in SMR. Funding Acknowledgement Type of funding source: None

Introduction The evaluation of functional significance in serial coronary lesions is crucial for achieving optimal clinical outcomes. In this setting, fractional flow reserve (FFR) measurements with pullback pressure recording can be helpful in assessing lesion functional significance. Purpose To describe the functional characteristics of angiography-defined serial coronary lesions using FFR-derived motorised pullback tracings, and to describe the Pullback Pressure Gradients (PPG) index - in these lesions. Methods Prospective, multicentre study with independent core laboratory analysis. Patients undergoing coronary angiography due to stable angina were enrolled. Serial lesions were defined angiographically as the presence of 2 or more narrowings with visual diameter stenosis >50% separated at least by 3 times the reference vessel diameter in the same coronary vessel. Continuous IV adenosine-FFR measurements were obtained using a motorised device at a speed of 1 mm/s. Pullback curves were assessed to determine the presence of focal step-ups (FFR >0.05 units over 20 mm). In addition, the PPGindex was computed for all vessels. PPGindex values close to 0 define functional diffuse disease whereas values close to 1 define focal disease. Results From a total of 159 vessels (117 patients), 25 vessels were adjudicated as presenting serial lesions (mean PPGindex 0.48±0.17, range 0.26–0.87). Two focal pressure step-ups were observed in 40% of the cases (n=10; mean PPGindex 0.59±0.17), whereas 8% of the vessels presented a progressive pressure losses (n=2; mean PPGindex 0.27±0.01). In the remaining 52% of the cases, a single pressure step-up was recorded (n=13; mean PPGindex 0.44±0.12; ANOVA p-value = 0.01). The PPGindex independently predicted the presence of two focal pressure step ups. Conclusion Hyperemic FFR curves in tandem stenoses revealed high prevalence of functional diffuse CAD. Two pressure step-ups occurred in less than half of the vessels. High PPG-Index identified vessels with two focal pressure drops. FFR tracings and the PPGindex provide a more objective CAD evaluation, which can lead to changes in the therapeutic approach. Funding Acknowledgement Type of funding source: None

Background and aim Hyperemic absolute coronary blood flow (in mL/min) can be safely and reproducibly measured with intracoronary continuous thermodilution of saline at room temperature at an infusion rate of 20 mL/min. This study aims at assessing whether continuous thermodilution can also measure resting flow and microvascular resistance. Methods and results In 87 coronary arteries (58 patients) with angiographic non-significant stenoses absolute flow was assessed by continuous thermodilution of saline at infusion rates of 10 mL/min and 20 mL/min using a pressure/temperature sensored guide wire, a dedicated infusion catheter and a dedicated software. In addition, in 26 arteries, average peak velocity (APV) was measured simultaneously using an intracoronary Doppler-wire. There was no significant difference between Pd/Pa at baseline and during saline infusion at 10 mL/min, (0.95±0.053 vs 0.94±0.054, respectively (p=0.53) and there was no significant difference in APV at baseline and during the infusion of saline at 10 mL/min (22.2±8.40 vs 23.2±8.39 cm/s, respectively, p=0.63), thus indicating presence of resting coronary blood flow during the infusion of 10 mL/min of saline. In contrast, at an infusion rate of 20 mL/min, a significant decrease in Pd/Pa was observed compared to baseline: (0.85±0.089 vs 0.95±0.053, respectively, p Conclusion Absolute coronary blood flow (in mL/min) can be measured by continuous thermodilution both at rest and during hyperemia. This allows accurate, reproducible, and operator-independent direct volumetric calculation of CFR and MRR. The latter is a quantitative metric which is specific for microvascular function and independent from myocardial mass. Doppler and Thermodilution derived MRR Funding Acknowledgement Type of funding source: None

Context Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown. Objective To characterize bone geometry, volumetric density and microarchitecture in CHH/KS. Methods This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture. Results CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia. Conclusion Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis.

Syndromic craniosynostoses are defined by the premature fusion of one or more cranial and facial sutures, leading to skull vault deformation, and midfacial retrusion. More recently, mandibular shape modifications have been described in FGFR-related craniosynostoses, which represent almost 75 % of the syndromic craniosynostoses. Here, further characterisation of the mandibular phenotype in FGFR-related craniosynostoses is provided in order to confirm mandibular shape modifications, as this could contribute to a better understanding of the involvement of the FGFR pathway in craniofacial development. The aim of our study was to analyse early mandibular morphology in a cohort of patients with FGFR2- (Crouzon and Apert) and FGFR3- (Muenke and Crouzonodermoskeletal) related syndromic craniosynostoses. We used a comparative geometric morphometric approach based on 3D imaging. Thirty-one anatomical landmarks and eleven curves with sliding semi-landmarks were defined to model the shape of the mandible. In total, 40 patients (12 with Crouzon, 12 with Apert, 12 with Muenke and 4 with Crouzonodermoskeletal syndromes) and 40 age and sex-matched controls were included (mean age: 13.7 months ± 11.9). Mandibular shape differed significantly between controls and each patient group based on geometric morphometrics. Mandibular shape in FGFR2-craniosynostoses was characterized by open gonial angle, short ramus height, and high and prominent symphysis. Short ramus height appeared more pronounced in Apert than in Crouzon syndrome. Additionally, narrow inter-condylar and inter-gonial distances were observed in Crouzon syndrome. Mandibular shape in FGFR3-craniosynostoses was characterized by high and prominent symphysis and narrow inter-gonial distance. In addition, narrow condylar processes affected patients with Crouzonodermoskeletal syndrome. Statistical analysis of variance showed significant clustering of Apert and Crouzon, Crouzon and Muenke, and Apert and Muenke patients (p Our results confirm distinct mandibular shapes at early ages in FGFR2- (Crouzon and Apert syndromes) and FGFR3-related syndromic craniosynostoses (Muenke and Crouzonodermoskeletal syndromes) and reinforce the hypothesis of genotype-phenotype correspondence concerning mandibular morphology.