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Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at high risk of chemotherapy-induced toxicity ,raising interest in less toxic anti-HER2 therapy regimens.Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed. T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6months, already reported (Lancet Oncol 2018, Wildiers et al). We now present data on long term outcome (including cause of death), and on response and tolerance of T-DM1 given after progression on TP(M).Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior (neo)adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 70% and/or to short physical performance battery ( 0 in 41%. With 54.0 months of median follow-up, 6-month PFS was 43.1% (95% CI 27.1-58.1) versus 73.0% (95% CI 55.8-84.3) for TP and TPM, respectively. 12-month PFS was 33.7% and 51.9%, and 24-month PFS 18.7% and 28.7%, respectively. A total of 49 (61.3%) patients died, 27 (69.2%) in the TP arm and 22 (53.7%) in the TPM arm. There was no significant difference in OS between the two arms (TPM vs TP: HR=0.72, 95% CI 0.41-1.26) with median OS 32.1 months for TP, and 37.5 months for TPM. The causes of death were progressive disease (N=37, 75.5%), toxicity (cardiac failure, N=1, 2.0%), and other causes not due to PD/toxicity (N=9, 22.5%). Among the 40 patients who have started T-DM1 (22 in TPM arm and 18 in TP arm), median follow-up was 33.7 months from T-DM1 start. PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5). Grade 3 or higher AE occurred in 18 pts (45%). Most relevant reported grade III or higher toxicities on T-DM1 were fatigue (N=3), anorexia (N=2), anemia (N=1), febrile neutropenia (N=1), diarrhoea (N=1), hepatic failure (N=1), lung infection (N=1), increased GGT (N=1), thrombocytopenia (N=1), weight loss (N=1), hypophosphatemia (N=1), dyspnoea (N=1), epistaxis (N=1), hematoma (N=1). Two patients (5%) experienced grade 5 toxicity: one death was considered as related to cachexia and tumor progression; the other death was considered to be related to acute pneumonia and renal failure. The prognostic impact of geriatric assessment on PFS and OS, and frailty evolution during therapy will be presented at the meeting.Conclusions: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years despite the associated frailty in the majority of the study population. T-DM1 provides a PFS rate at 6 months of 43.6% (95% CI: 27.7-58.5) with a wide range of possibly related toxicities in this generally frail population. Citation Format: Hans Wildiers, Sandrine Marreaud, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Bart Meulemans, Berta Sousa, Coralie Poncet, Etienne Brain. Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer, followed by T-DM1 after progression [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-06.

© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).

Objective To describe the antenatal and pathological features of an immature umbilical cord teratoma associated with exomphalos, and to review the literature on this subject. Case presentation An abdominal wall defect, suspected to be an exomphalos, was identified during routine ultrasound examination performed at 13 weeks of gestation. The pregnancy was terminated. Fetopathological examination revealed an immature umbilical cord teratoma associated with exomphalos. Chromosomal microarray analysis was normal. Conclusions Umbilical cord teratomas, albeit very rare, should be emphasized as a possible differential diagnosis when abdominal wall defects are detected. Since cord teratomas may lead to adverse fetal or neonatal outcomes, close follow-up of the fetus is recommended.

Pathogenic variants in the NGLY1 gene are associated with a Congenital Disorder of Deglycosylation (CDDG) characterized by delays in reaching developmental milestones, complex hyperkinetic movement disorder, transient elevation of transaminases, and alacrima or hypolacrima. To date, only few cases of NGLY1 deficiency have been identified and reported in the literature. This report highlights a first child of non‐consanguineous parents with no relevant family history who presented with hypotonia and poor weight gain since birth. At 2 months, the child developed paroxysmal cervical dystonia, posteriorly resolving spontaneously by age of 3. Subsequently, delays in reaching developmental milestones, ataxia, dyskinesia, visual impairment due to cone rod retinal dystrophy, low triglycerides, and persistently elevated liver transaminases were observed. Extensive etiological investigation was performed, including array‐CGH and metabolic evaluation with no abnormalities to note. Trio whole exome analysis identified a homozygous pathogenic variant of the NGLY1 gene, c.1891del (p.Gln631Serfs*7), consistent with CDDG. Both parents were confirmed to be heterozygous carriers. The authors discuss in this case, the clinical presentation, the diagnostic challenges, and review other relevant NGLY1 deficiency cases previously reported in the literature. This case, along with the previous reported in the literature, indicates that pathogenic variants in NGLY1 cause a recognizable phenotype and should be considered in patients with a typical presentation. It also suggests that decreased sweating is not present universally in these patients.

Objective: To describe the ultrasonographic, pathologic and molecular findings in a fetus with TAR syndrome, and to illustrate the contribution of chromosomal microarray analysis (CMA) to the etiological investigation of fetal upper limb reduction defects. Case report: A 35-year-old woman was referred for Genetic Counseling after pregnancy termination for severe upper limb bilateral phocomelia detected in the second trimester. Fetal autopsy showed severe shortening of the arms and forearms. The fetal skeletal survey confirmed the absence of the radii, ulnae and humeri. CMA revealed an interstitial deletion in 1q21 including the RBM8A gene. Subsequent Sanger sequencing of this gene identified a hypomorphic mutant allele, c.-21G > A, confirming the diagnosis of TAR syndrome. Conclusion: The differential diagnosis of upper limb defects is broad. Identification of their cause is essential for adequate genetic counseling including prognosis and recurrence risk estimation. CMA should be considered in fetuses with upper limb reduction defects, especially when the thumbs are present. Keywords: 1q21.1 microdeletion, Limb reduction defects, Phocomelia, RBM8A, Thrombocytopenia-absent radius (TAR) syndrome

The current study aimed to track the trajectory of quality of life (QoL) among subgroups of women with breast cancer in the first 12 months post-diagnosis. We also aimed to assess the number and portion of women classified into each distinct trajectory and the sociodemographic, clinical, and psychosocial factors associated with these trajectories. The international sample included 699 participants who were recruited soon after being diagnosed with breast cancer as part of the BOUNCE Project. QoL was assessed at baseline and after 3, 6, 9, and 12 months, and we used Latent Class Growth Analysis to identify trajectory subgroups. Sociodemographic, clinical, and psychosocial factors at baseline were used to predict latent class membership. Four distinct QoL trajectories were identified in the first 12 months after a breast cancer diagnosis: medium and stable (26% of participants); medium and improving (47%); high and improving (18%); and low and stable (9%). Thus, most women experienced improvements in QoL during the first year post-diagnosis. However, approximately one-third of women experienced consistently low-to-medium QoL. Cancer stage was the only variable which was related to the QoL trajectory in the multivariate analysis. Early interventions which specifically target women who are at risk of ongoing low QoL are needed.

Intellectual developmental disorder with dysmorphic facies and behavioral abnormalities (IDDFBA) is a recently described autosomal dominant entity caused by pathogenic variants, mostly de novo, in the FBXO11 gene. It presents in the first years of life with highly variable clinical manifestations. The main features of IDDFBA include borderline-to-severe intellectual disability, behavioral problems, hypotonia, facial dysmorphisms, minor skeletal abnormalities, and recurrent infections. Although eye problems, such as refractive errors, eye misalignment and minor visual changes, have been described in about 48% of patients, a major ocular defect, namely, bilateral optic nerve hypoplasia, has been reported in the literature only once. We report an 8-year-old boy with a novel de novo pathogenic variant in FBXO11 gene (NM_001190274.1: c.1166dup, p.Cys390Metfs∗3) and a complex ophthalmological phenotype, consisting of right microphthalmia, very shallow anterior chamber, and persistent pupillary membrane, right dense nuclear cataract, bilateral optic nerve hypoplasia, and bilateral horizontal manifest nystagmus. info:eu-repo/semantics/publishedVersion

Proper and well-timed interventions may improve breast cancer patient adaptation, resilience and quality of life (QoL) during treatment process and time after disease. The challenge is to identify those patients who would benefit most from a particular intervention. The aim of this study was to measure whether the machine learning prediction incorporated in the clinical decision support system (CDSS) improves clinicians' performance to predict patients' QoL during treatment process. We conducted an experimental setup in which six clinicians used CDSS and predicted QoL for 60 breast cancer patients. Each patient was evaluated both with and without the aid of machine learning prediction. The clinicians were also open-ended interviewed to investigate the usage and perceived benefits of CDSS with the machine learning prediction aid. Clinicians' performance to evaluate the patients' QoL was higher with the aid of machine learning predictions than without the aid. AUROC of clinicians was .777 (95% CI .691 - .857) with the aid and .755 (95% CI .664 - .840) without the aid. When the machine learning model's prediction was correct, the average accuracy (ACC) of the clinicians was .788 (95% CI .739 - .838) with the aid and .717 (95% CI .636 - .798) without the aid.

Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in DOCK8 (26 patients), STAT3 (21), STAT1 (15), CARD9 (6), AIRE (3), IL17RA (2), SPINK5 (3), ZNF341 (2), CARMIL2/RLTPR (1), IL12RB1 (1), and WAS (1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers., Projekt DEAL; German Ministry of Education and Research (BMBF) [01E01303, 01ZX1306F, 01ZX1306A]; E-rare program of the European Commission EURO-CMC [01GM1502]; German Center for Infection Research DZIF [8000805-3, TTU-IICH_07.801]; German Research Foundation (DFG) [390939984, 39087428], Open Access funding enabled and organized by Projekt DEAL. Financial support for this research came from the German Ministry of Education and Research (BMBF, grant no. 01E01303; sys-INFLAME grant nos. 01ZX1306F and 01ZX1306A), from the E-rare program of the European Commission EURO-CMC (01GM1502), and from the German Center for Infection Research DZIF (8000805-3 and TTU-IICH_07.801). This study was supported by the German Research Foundation (DFG) under Germany's Excellence Strategy CIBSS (EXC-2189) (Project ID 390939984) and RESIST (EXC 2155) (Project ID 39087428).

Pathogenic variants in INPP5E cause Joubert syndrome (JBTS), a ciliopathy with retinal involvement. However, despite sporadic cases in large cohort sequencing studies, a clear association with non-syndromic inherited retinal degenerations (IRDs) has not been made. We validate this association by reporting 16 non-syndromic IRD patients from ten families with bi-allelic mutations in INPP5E. Additional two patients showed early onset IRD with limited JBTS features. Detailed phenotypic description for all probands is presented. We report 14 rare INPP5E variants, 12 of which have not been reported in previous studies. We present tertiary protein modeling and analyze all INPP5E variants for deleteriousness and phenotypic correlation. We observe that the combined impact of INPP5E variants in JBTS and non-syndromic IRD patients does not reveal a clear genotype–phenotype correlation, suggesting the involvement of genetic modifiers. Our study cements the wide phenotypic spectrum of INPP5E disease, adding proof that sequence defects in this gene can lead to early-onset non-syndromic IRD.

Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development. info:eu-repo/semantics/publishedVersion

Background: Axillary staging in patients with complete response after neoadjuvant chemotherapy (NAC) is still controversial. Our objective was to test tattoo alone and subsequentially tattoo plus clip as markers in the targeted axillary dissection of ycN0 patients. Methods: Prospective cohort of cT1-T3, cN1 (proven histologically), M0 patients scheduled to receive NAC. Exclusion criteria were lobular histology, prior axillary surgery, and clinical N2/3. In cohort 1 this positive node (Neotarget node) was tattooed at diagnosis. If ycN0, a targeted axillary dissection was performed. After an interim analysis with negative results we changed the protocol in order to do a double marking procedure (Cohort 2): the positive node was clipped at diagnosis and after NAC a tattoo was done before surgery. Results: Thirteen patients in Cohort 1 and 18 patients in Cohort 2. Failure to identify the Neotarget node with multiple nodes retrieved in 9/13 (69%) of Cohort 1 patients. Also in 5/13 (38%) of Cohort 1 patients and 3/18 (17%) of Cohort 2 there was a failure to clearly identify tattooed nodes. In Cohort 2, clip identification by surgical specimen radiography allowed the identification of the tagged node in 17/18 (94,4%) of cases. The concordance between the clipped node and sentinel nodes was 16/18 (89%). Conclusions: The introduction of double marking by clipping the metastatic node and verifying their removal by surgical specimen radiography, using carbon ink as a tracer, allowed the identification of the metastatic node in 94% of cases, with a simple, reproducible, and easy-to-implement targeted axillary dissection procedure.

© The Author(s) 2021. Open AccessThis article is licensed under a Creative CommonsAttribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the CreativeCommons license, and indicate if changes were made. The images or other third partymaterial in this article are included in the article’s Creative Commons license, unlessindicated otherwise in a credit line to the material. If material is not included in thearticle’s Creative Commons license and your intended use is not permitted by statutoryregulation or exceeds the permitted use, you will need to obtain permission directly fromthe copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/., Homozygosity mapping is a powerful method for identifying mutations in patients with recessive conditions, especially in consanguineous families or isolated populations. Historically, it has been used in conjunction with genotypes from highly polymorphic markers, such as DNA microsatellites or common SNPs. Traditional software performs rather poorly with data from Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS), which are now extensively used in medical genetics. We develop AutoMap, a tool that is both web-based or downloadable, to allow performing homozygosity mapping directly on VCF (Variant Call Format) calls from WES or WGS projects. Following a training step on WES data from 26 consanguineous families and a validation procedure on a matched cohort, our method shows higher overall performances when compared with eight existing tools. Most importantly, when tested on real cases with negative molecular diagnosis from an internal set, AutoMap detects three gene-disease and multiple variant-disease associations that were previously unrecognized, projecting clear benefits for both molecular diagnosis and research activities in medical genetics.

Purpose Pseudoxanthoma elasticum (PXE) is a recessive disorder involving skin, eyes and arteries, mainly caused by ABCC6 pathogenic variants. However, almost one fifth of patients remain genetically unsolved despite extensive genetic screening of ABCC6, as illustrated in a large French PXE series of 220 cases. We searched for new PXE gene(s) to solve the ABCC6-negative patients. Methods First, family-based exome sequencing was performed, in one ABCC6-negative PXE patient with additional neurological features, and her relatives. CYP2U1, involved in hereditary spastic paraplegia type 56 (SPG56), was selected based on this complex phenotype, and the presence of two candidate variants. Second, CYP2U1 sequencing was performed in a retrospective series of 46 additional ABCC6-negative PXE probands. Third, six additional SPG56 patients were evaluated for PXE skin and eye phenotype. Additionally, plasma pyrophosphate dosage and functional analyses were performed in some of these patients. Results 6.4% of ABCC6-negative PXE patients (n=3) harbored biallelic pathogenic variants in CYP2U1. PXE skin lesions with histological confirmation, eye lesions including maculopathy or angioid streaks, and various neurological symptoms were present. CYP2U1 missense variants were confirmed to impair protein function. Plasma pyrophosphate levels were normal. Two SPG56 patients (33%) presented some phenotypic overlap with PXE. Conclusion CYP2U1 pathogenic variants are found in unsolved PXE patients with neurological findings, including spastic paraplegia, expanding the SPG56 phenotype and highlighting its overlap with PXE. The pathophysiology of ABCC6 and CYP2U1 should be explored to explain their respective role and potential interaction in ectopic mineralization.

PurposePathogenic variants in INPP5E cause Joubert syndrome, a systemic disorder that can manifest with retinal degeneration among other clinical features. We aimed to evaluate the role of INPP5E variants in non-syndromic inherited retinal degenerations (IRDs) of varying severity.MethodsTargeted or genome sequencing were performed in 12 unrelated non-syndromic IRD families from multiple research hospitals. Detailed clinical examination was conducted in all probands. The impact of new likely pathogenic variants was modeled on a tertiary INPP5E protein structure and all the new and published variants were analyzed for their deleteriousness and phenotypic correlation.ResultsFourteen INPP5E rare alleles were detected, 12 of which were novel. Retinal degeneration in all 12 probands was clinically distinguishable on the basis of onset and severity into Leber congenital amaurosis (n=4) and a milder, later-onset rod-cone dystrophy (n=8). Two probands showed mild ciliopathy features that resolved in childhood. Analysis of the combined impact of both alleles in syndromic and non-syndromic INPP5E patients did not reveal clear genotype-phenotype correlation, suggesting involvement of genetic modifiers.ConclusionsThe study expands the phenotypic spectrum of disorders due to pathogenic variants in INPP5E and describes a new disease association with previously underdiagnosed forms of early-onset non-syndromic IRD.

The 21st annual meeting of the Portuguese Society of Human Genetics (SPGH), organized by Luísa Romão, Ana Sousa and Rosário Pinto Leite, was held in Caparica, Portugal, from the 16th to the 18th of November 2017. Having entered an era in which personalized medicine is emerging as a paradigm for disease diagnosis, treatment and prevention, the program of this meeting intended to include lectures by leading national and international scientists presenting exceptional findings on the genetics of personalized medicine. Various topics were discussed, including cancer genetics, transcriptome dynamics and novel therapeutics for cancers and rare disorders that are designed to specifically target molecular alterations in individual patients. Several panel discussions were held to emphasize (ethical) issues associated with personalized medicine, including genetic cancer counseling. info:eu-repo/semantics/publishedVersion

Patients with estrogen receptor-positive (ER +) early breast cancer (EBC) are at a continuous risk for distant relapse despite 5 years of standard endocrine therapy, even after 10–15 years after primary diagnosis. Hence, large randomized clinical trials were conducted to evaluate the role of extended endocrine treatment (ET) with the primary goal to prevent or at least delay distant relapse. Two very large trials of extended tamoxifen (TAM), the ATLAS and the aTTom trial, proved the efficacy of prolonged TAM particularly important after 10 years due to the carry-over effect of the five initial years. Additionally, the extended use of AIs after 5 years of tamoxifen, also proved to be efficacious in preventing late distant relapses. For letrozole (LET) it was shown in the MA.17 trial that it also improves overall survival (OS) in node-positive BC patients. There are many options and still unanswered questions related to extended ET, which are discussed in this review. The most important issue in deciding prolonged duration of ET is undoubtfully how to identify ER+ patients who benefit most from this approach. With this purpose, not only classical pathological factors have been studied, but also molecular profiles of individual tumors, which might help us in the near future to better tailor ET. Not only efficacy, but also toxicity of such prolonged treatment is essential for optimal use, particularly maintained compliance in a routine clinical practice. These issues are discussed in this review.

INTRODUCTION: Epileptic encephalopathies of childhood are characterized by early seizure-onset and adverse neurological outcomes. The development of new genetic techniques has allowed an exponential identification of the genes that are involved. Over the last years, we have observed a revolution in the diagnostic paradigm. However, there are no international guidelines regarding the diagnosis of genetic epileptic encephalopathies. We aim to discuss the current knowledge about the genetic architecture of epileptic encephalopathies of childhood. MATERIAL AND METHODS: review of the literature about infantile epileptic encephalopathies and the genetic tests currently available. A systematic approach and a diagnostic algorithm to use in clinical practice were proposed. RESULTS: Initially the patient's phenotype should be determined based on the seizure type, electroencephalogram pattern and neuroimaging. Patients with unclear etiology after brain magnetic resonance imaging should undergo an appropriate metabolic investigation to promptly exclude treatable conditions. Further studies should also include other genetic causes, mainly if associated with particular phenotypic features. Chromosomal microarray analysis should be firstly considered, particularly if dysmorphic or polymalformative abnormalities are present. If this is negative and/or there are no physical features, the next step should be next-generation sequencing multigene panels or whole-exome sequencing. Single gene study should only be considered when the patient's phenotype is highly suggestive of a specific syndrome. CONCLUSION: The revolution of the genetic knowledge about epileptic encephalopathies of childhood has led to a complex diagnostic approach. This new paradigm poses significant implications in genetic counselling, treatment and prognosis. Introdução: As encefalopatias epilépticas da infância constituem um grupo de patologias de início precoce e prognóstico neurológico reservado. O desenvolvimento das novas técnicas de estudo genético foi responsável pela identificação de novos genes implicados. Nos últimos anos, assistimos a uma revolução no seu paradigma diagnóstico. Contudo, actualmente não existem recomendações internacionais consensuais sobre a abordagem à investigação das encefalopatias epilépticas genéticas. Pretendemos discutir o conhecimento actual sobre a arquitectura genética das encefalopatias epilépticas infantis. Material e Métodos: Realizou-se uma revisão da literatura das encefalopatias epilépticas infantis genéticas e estudos utilizados no seu diagnóstico. Propomos uma abordagem sistematizada através de um algoritmo diagnóstico a utilizar na prática clínica. Resultados: Inicialmente deve-se determinar o fenótipo do doente com base no tipo de crises, padrão electroencefalográfico e neuroimagem. Nos doentes sem etiologia após resultados de ressonância magnética cranioencefálica, deve-se realizar estudo metabólico apropriado para o diagnóstico prioritário de doenças metabólicas tratáveis. A investigação de outras causas genéticas deve ser considerada, sobretudo perante características fenotípicas sugestivas. Primeiro deve-se realizar a análise de microarray cromossómico, principalmente se existirem alterações dismórficas ou polimalformativas. Se esta for negativa e/ou não existirem elementos físicos distintivos, o próximo passo deve ser realizar os painéis multigénicos ou sequenciação de exoma. Os estudos dirigidos do gene devem ser reservados para quando o fenótipo é indicativo de uma síndrome específica. Conclusão: A marcha diagnóstica das encefalopatias epilépticas tornou-se complexa com a expansão de conhecimentos genéticos. Este novo paradigma apresenta implicações terapêuticas, prognósticas e de aconselhamento familiar. info:eu-repo/semantics/publishedVersion

Copyright © 2020, American College of Medical Genetics and Genomics, Purpose: Determination of genotypic/phenotypic features of GATAD2B-associated neurodevelopmental disorder (GAND). Methods: Fifty GAND subjects were evaluated to determine consistent genotypic/phenotypic features. Immunoprecipitation assays utilizing in vitro transcription-translation products were used to evaluate GATAD2B missense variants' ability to interact with binding partners within the nucleosome remodeling and deacetylase (NuRD) complex. Results: Subjects had clinical findings that included macrocephaly, hypotonia, intellectual disability, neonatal feeding issues, polyhydramnios, apraxia of speech, epilepsy, and bicuspid aortic valves. Forty-one novelGATAD2B variants were identified with multiple variant types (nonsense, truncating frameshift, splice-site variants, deletions, and missense). Seven subjects were identified with missense variants that localized within two conserved region domains (CR1 or CR2) of the GATAD2B protein. Immunoprecipitation assays revealed several of these missense variants disrupted GATAD2B interactions with its NuRD complex binding partners. Conclusions: A consistent GAND phenotype was caused by a range of genetic variants in GATAD2B that include loss-of-function and missense subtypes. Missense variants were present in conserved region domains that disrupted assembly of NuRD complex proteins. GAND's clinical phenotype had substantial clinical overlap with other disorders associated with the NuRD complex that involve CHD3 and CHD4, with clinical features of hypotonia, intellectual disability, cardiac defects, childhood apraxia of speech, and macrocephaly., Research reported in this paper was supported by the National Institutes of Health (NIH) Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number U01HG007672. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. GAND50’s seq+ analysis was supported by NIH National Center for Advancing Translational Science (NCATS) UCLA Clinical and Translational Science Institute (CTSI) grant number UL1TR001881. J.P.M. received funding from the National Health and Medical Research Council (APP1012161, APP1063301, APP1126357, APP1058916). T.M.P. and this research was supported by the Cedars-Sinai institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program. T.M.P. is especially grateful for the wonderful and continued support from the Cedars-Sinai Fashion Industries Guild.

Epileptic encephalopathies of childhood are characterized by early seizure-onset and adverse neurological outcomes. The development of new genetic techniques has allowed an exponential identification of the genes that are involved. Over the last years, we have observed a revolution in the diagnostic paradigm. However, there are no international guidelines regarding the diagnosis of genetic epileptic encephalopathies. We aim to discuss the current knowledge about the genetic architecture of epileptic encephalopathies of childhood.review of the literature about infantile epileptic encephalopathies and the genetic tests currently available. A systematic approach and a diagnostic algorithm to use in clinical practice were proposed.Initially the patient's phenotype should be determined based on the seizure type, electroencephalogram pattern and neuroimaging. Patients with unclear etiology after brain magnetic resonance imaging should undergo an appropriate metabolic investigation to promptly exclude treatable conditions. Further studies should also include other genetic causes, mainly if associated with particular phenotypic features. Chromosomal microarray analysis should be firstly considered, particularly if dysmorphic or polymalformative abnormalities are present. If this is negative and/or there are no physical features, the next step should be next-generation sequencing multigene panels or whole-exome sequencing. Single gene study should only be considered when the patient's phenotype is highly suggestive of a specific syndrome.The revolution of the genetic knowledge about epileptic encephalopathies of childhood has led to a complex diagnostic approach. This new paradigm poses significant implications in genetic counselling, treatment and prognosis.Introdução: As encefalopatias epilépticas da infância constituem um grupo de patologias de início precoce e prognóstico neurológico reservado. O desenvolvimento das novas técnicas de estudo genético foi responsável pela identificação de novos genes implicados. Nos últimos anos, assistimos a uma revolução no seu paradigma diagnóstico. Contudo, actualmente não existem recomendações internacionais consensuais sobre a abordagem à investigação das encefalopatias epilépticas genéticas. Pretendemos discutir o conhecimento actual sobre a arquitectura genética das encefalopatias epilépticas infantis.Material e Métodos: Realizou-se uma revisão da literatura das encefalopatias epilépticas infantis genéticas e estudos utilizados no seu diagnóstico. Propomos uma abordagem sistematizada através de um algoritmo diagnóstico a utilizar na prática clínica.Resultados: Inicialmente deve-se determinar o fenótipo do doente com base no tipo de crises, padrão electroencefalográfico e neuroimagem. Nos doentes sem etiologia após resultados de ressonância magnética cranioencefálica, deve-se realizar estudo metabólico apropriado para o diagnóstico prioritário de doenças metabólicas tratáveis. A investigação de outras causas genéticas deve ser considerada, sobretudo perante características fenotípicas sugestivas. Primeiro deve-se realizar a análise de microarray cromossómico, principalmente se existirem alterações dismórficas ou polimalformativas. Se esta for negativa e/ou não existirem elementos físicos distintivos, o próximo passo deve ser realizar os painéis multigénicos ou sequenciação de exoma. Os estudos dirigidos do gene devem ser reservados para quando o fenótipo é indicativo de uma síndrome específica.Conclusão: A marcha diagnóstica das encefalopatias epilépticas tornou-se complexa com a expansão de conhecimentos genéticos. Este novo paradigma apresenta implicações terapêuticas, prognósticas e de aconselhamento familiar.

Introduction: Thyroid hormones have an important role in the regulation of lipid metabolism. Higher levels of TSH could be associated with impaired lipid profile and cardiovascular disease, even with normal levels of free thyroxine (FT4). The aim of this study was to investigate the association between TSH levels and lipid profile in patients with primary hypothyroidism. Materials and methods: Retrospective evaluation of patients with primary hypothyroidism treated with levothyroxine (LT4), with normal levels of FT4. Patients with known dyslipidemia were excluded. Thyroid function, total cholesterol (TC), triglycerides (Tg), HDL-cholesterol (HDL) and LDL-cholesterol (LDL) were studied. Patients were divided according to their TSH levels: 0.05) and lower mean LDL levels (96.3mg/dL vs 106.7mg/dL, p>0.05). TSH values positively correlated with higher TC levels (r=0.319, p

The COVID-19 pandemic has important consequences for the mental health of populations. Patients with cancer, already at risk for poor mental health outcomes, are not expected to be spared from these consequences, prompting the need for health services to improve responsiveness. This article presents the research protocol for an implementation study designed to describe the uptake of a well-studied and recognized system for the treatment of depression and anxiety (Stepped-care) during the specific context of a Pandemic in an oncological site. The system set-up will be assisted by a digital platform (MoodUP), where patients undergoing cancer treatment will be screened for anxiety and depressive symptoms, triaged by severity level and algorithm-matched to recommended interventions. Patients undergoing cancer treatment at a cancer clinic in Portugal will be invited to subscribe to the MoodUP platform where they will complete a self-reported questionnaire (Hospital Anxiety and Depression Scale) to screen their anxiety and depressive symptoms. Data will be instantly collected, and an algorithm will activate severity-matched intervention suggestions, through a case manager that will coordinate care. The specific objectives of this study will be to describe the implementation and acceptability of the care system by patients and staff, the barriers to and facilitators of implementation, the proportion of patients accessing the system and their pathways through the various stepped-care interventions, and patient perceptions regarding the feasibility and appropriateness of the eHealth platform. Moreover, exploratory analyses will be conducted to describe patterns of anxiety and depression symptoms variation across all patients, as well as within sociodemographically, clinically and contextually characterized subgroups, to characterize their care needs and access, as well as to explore for whom the MoodUP care system may be more appropriate. This study is expected to improve processes for collaborative mental healthcare in oncology and accelerate the digitalization of services, towards the improvement of mental healthcare access, and management of high-risk patients, during the COVID-19 pandemic.

© 2019 Silva, Fonseca, Pereira, Silva, Barbosa, Serra-Caetano, Blanco, Rosmaninho, Pérez-Andrés, Sousa, Raposo, Gama-Carvalho, Victorino, Hammarstrom and Sousa., Monozygotic twins provide a unique opportunity to better understand complex genetic diseases and the relative contribution of heritable factors in shaping the immune system throughout life. Common Variable Immunodeficiency Disorders (CVID) are primary antibody defects displaying wide phenotypic and genetic heterogeneity, with monogenic transmission accounting for only a minority of the cases. Here, we report a pair of monozygotic twins concordant for CVID without a family history of primary immunodeficiency. They featured a remarkably similar profile of clinical manifestations and immunological alterations at diagnosis (established at age 37) and along the subsequent 15 years of follow-up. Interestingly, whole-exome sequencing failed to identify a monogenic cause for CVID, but unraveled a combination of heterozygous variants, with a predicted deleterious impact. These variants were found in genes involved in relevant immunological pathways, such as JUN, PTPRC, TLR1, ICAM1, and JAK3. The potential for combinatorial effects translating into the observed disease phenotype is inferred from their roles in immune pathways, namely in T and B cell activation. The combination of these genetic variants is also likely to impose a significant constraint on environmental influences, resulting in a similar immunological phenotype in both twins, despite exposure to different living conditions. Overall, these cases stress the importance of integrating NGS data with clinical and immunological phenotypes at the single-cell level, as provided by multi-dimensional flow-cytometry, in order to understand the complex genetic landscape underlying the vast majority of patients with CVID, as well as those with other immunodeficiencies., This work received funding from PAC - PRECISE - LISBOA01-0145-FEDER-016394, co-funded by FEDER through POR Lisboa 2020 - Programa Operacional Regional de Lisboa PORTUGAL 2020 and Fundação para a Ciência e a Tecnologia; and UID/BIM/50005/2019, project funded by Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES) through Fundos do Orçamento de Estado. Work in MG-C lab is supported by UID/MULTI/04046/2019 Research Unit grant from FCT, Portugal (to BioISI) and FCT research grant PTDC/BIA-CEL/29257/2017.

Whereas the vast majority of osteogenesis imperfecta (OI) is caused by autosomal dominant defects in the genes encoding type I procollagen, mutations in a myriad of genes affecting type I procollagen biosynthesis or bone formation and homeostasis have now been associated with rare autosomal recessive OI forms. Recently, homozygous or compound heterozygous mutations in BMP1, encoding the metalloproteases bone morphogenetic protein-1 (BMP1) and its longer isoform mammalian Tolloid (mTLD), were identified in 5 children with a severe autosomal recessive form of OI and in 4 individuals with mild to moderate bone fragility. BMP1/mTLD functions as the procollagen carboxy-(C)-proteinase for types I to III procollagen but was also suggested to participate in amino-(N)-propeptide cleavage of types V and XI procollagens and in proteolytic trimming of other extracellular matrix (ECM) substrates. We report the phenotypic characteristics and natural history of 4 adults with severe, progressive OI characterized by numerous fractures, short stature with rhizomelic shortening, and deformity of the limbs and variable kyphoscoliosis, in whom we identified novel biallelic missense and frameshift mutations in BMP1. We show that BMP1/mTLD-deficiency in humans not only results in delayed cleavage of the type I procollagen C-propeptide but also hampers the processing of the small leucine-rich proteoglycan prodecorin, a regulator of collagen fibrillogenesis. Immunofluorescent staining of types I and V collagen and transmission electron microscopy of the dermis show impaired assembly of heterotypic type I/V collagen fibrils in the ECM. Our study thus highlights the severe and progressive nature of BMP1-associated OI in adults and broadens insights into the functional consequences of BMP1/mTLD-deficiency on ECM organization.

A epidermólise bolhosa juncional é uma genodermatose caracterizada por fragilidade cutânea e formação de erosões e bolhas a nível da junção dermo-epidérmica, após trauma minor. Reportamos o caso clínico de um recém-nascido, sexo masculino, caucasiano, com erupção cutânea caracterizada por bolhas tensas e erosões nas mãos, abdómen e couro cabeludo. Realizou-se uma biopsia cutânea para imunoflurescência directa com painel de anticorpos, que foi compatível com o diagnóstico de epidermólise bolhosa juncional não-Herlitz. No estudo genético identificou-se 2 mutações no gene COL17A1. Destaca-se nos antecedentes familiares, um irmão com dermatose bolhosa, falecido na terceira semana de vida por intercorrência infeciosa, sem ter sido possível efectuar o diagnóstico definitivo que possibilitasse o diagnóstico pré-natal. Salientamos a importância da referenciação rápida destes doentes a centros especializados, de forma a possibilitar o diagnóstico precoce desta patologia, uma orientação clínica adequada e um correto aconselhamento genético, incluindo o diagnóstico pré-natal em futuras gravidezes.

IntroductionPseudohypoparathyroidism is a genetically heterogeneous condition characterized by hypocalcemia and hyperphosphatemia resulting from end-organ resistance to parathyroid hormone (PTH). It is classified into several distinct entities (type Ia, Ib, Ic, type II), according to the molecular causes and clinical features of the patients.Case reportWe report a symptomatic case of a pediatric patient with hypocalcaemia, hyperphosphatemia, hypomagnesaemia and an elevated serum PTH level that presented with tetany. The molecular genetic test revealed a GNAS gene methylation defect of the A/B promoter, which confirms the diagnosis of a sporadic form of pseudohypoparathyroidism type Ib.

Variants in 11 genes of the RAS/MAPK signaling pathway have been causally linked to the neuro-cardio-facio-cutaneous syndromes group (NCFCS). Recently, A2ML1 and RIT1 were also associated with these syndromes. Because of the genetic and clinical heterogeneity of NCFCS, it is challenging to define strategies for their molecular diagnosis. The aim of this study was to develop and validate a massive parallel sequencing (MPS)-based strategy for the molecular diagnosis of NCFCS. A multiplex PCR-based strategy for the enrichment of the 13 genes and a variant prioritization pipeline was established. Two sets of genomic DNA samples were studied using the Ion PGM System: (1) training set (n =15) to optimize the strategy and (2) validation set (n = 20) to validate and evaluate the power of the new methodology. Sanger sequencing was performed to confirm all variants and low covered regions. All variants identified by Sanger sequencing were detected with our MPS approach. The methodology resulted in an experimental approach with a specificity of 99.0% and a maximum analytical sensitivity of ≥ 98.2% with a confidence of 99%. Importantly, two patients (out of 20) harbored described disease-causing variants in genes that are not routinely tested (RIT1 and SHOC2). The addition of less frequently altered genes increased in ≈ 10% the diagnostic yield of the strategy currently used. The presented workflow provides a comprehensive genetic screening strategy for patients with NCFCS in a fast and cost-efficient manner. This approach demonstrates the potential of a combined MPS-Sanger sequencing-based strategy as an effective diagnostic tool for heterogeneous diseases.

Three overlapping conditions, namely Rothmund-Thomson (RTS), Baller-Gerold (BGS) and RAPADILINO syndromes, have been attributed to RECQL4 mutations. Differential diagnoses depend on the clinical presentation, but the numbers of known genes remain low, leading to the widespread prescription of RECQL4 sequencing. The aim of our study was therefore to determine the best clinical indicators for the presence of RECQL4 mutations in a series of 39 patients referred for RECQL4 molecular analysis and belonging to the RTS (27 cases) and BGS (12 cases) spectrum. One or two deleterious RECQL4 mutations were found in 10/27 patients referred for RTS diagnosis. Clinical and molecular reevaluation led to a different diagnosis in 7/17 negative cases, including Clericuzio-type poikiloderma with neutropenia, hereditary sclerosing poikiloderma, and craniosynostosis/anal anomalies/porokeratosis. No RECQL4 mutations were found in the BGS group without poikiloderma, confirming that RECQL4 sequencing was not indicated in this phenotype. One chromosomal abnormality and one TWIST mutation was found in this cohort. This study highlights the search for differential diagnoses before the prescription of RECQL4 sequencing in this clinically heterogeneous group. The combination of clinically defined subgroups and next-generation sequencing will hopefully bring to light new molecular bases of syndromes with poikiloderma, as well as BGS without poikiloderma.

Objective To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith–Lemli–Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. Case report A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal – 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. Conclusion The differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.

Neoadjuvant therapy (NT) has become a valuable research tool for the incorporation of alternative cytotoxic agents, as well as new biological therapies, into anthracycline and taxane chemotherapy-based regimens. Her-2-positive disease is predictive of higher pathological complete response (pCR) to neoadjuvant chemotherapy and trastuzumab. Benefits were also seen for the combination of trastuzumab with lapatinib or pertuzumab, suggesting that dual blockage of the HER-2 will probably emerge as the new standard. Triple-negative phenotype is also predictive of high pCR to NT, but the prognosis of patients whose tumours do not achieve a pCR after neoadjuvant chemotherapy with anthracyclines and taxanes is dismal. Currently, it is recommended to use the same chemotherapy regimens as in non-triple-negative disease. The suggested benefit of neoadjuvant platinum, mainly in BRCA1-related cancers, needs to be confirmed in large randomized trials. Bevacizumab combined with neoadjuvant chemotherapy yields increased pCR compared with non-bevacizumab treatment, in large randomized data recently published. One study suggested higher benefit in triple-negative tumours. Long-term follow-up of these trials is needed to understand the role of bevacizumab treatment in BC and its important to find predictive biomarkers of response to this drug.