PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families.

Childhood-onset osteoporosis is a rare but clinically significant condition. Studies have shown pathogenic variants in more than 20 different genes as causative for childhood-onset primary osteoporosis. The X-chromosomal PLS3, encoding Plastin-3, is one of the more recently identified genes. In this study, we describe five new families from four different European countries with PLS3-related skeletal fragility. The index cases were all hemizygous males presenting with long bone and vertebral body compression fractures. All patients had low lumbar spine bone mineral density (BMD). The age at the first clinical fracture ranged from 1.5 to 13 years old. Three of the identified PLS3 variants were stop-gain variants and two were deletions involving either a part or all exons of the gene. In four families the variant was inherited from the mother. All heterozygous women reported here had normal BMD and no bone fractures. Four patients received bisphosphonate treatment with good results, showing a lumbar spine BMD increment and vertebral body reshaping after 10 months to 2 years of treatment. Our findings expand the genetic spectrum of PLS3-related osteoporosis. Our report also shows that early treatment with bisphosphonates may influence the disease course and reduce the progression of osteoporosis, highlighting the importance of early diagnosis for prompt intervention and appropriate genetic counseling.

Autoimmune hypothyroidism and trastuzumab therapy: a rare association.

Summary: We report a case of a woman with a diagnosis of breast cancer who unintentionally started gaining weight, feeling tired, and constipated 44 weeks after the initiation of trastuzumab. Hypothyroidism secondary to an autoimmune thyroiditis associated with trastuzumab was diagnosed, the first case described in Portugal and the fourth case described worldwide. Our intention regarding the publication of this case report is to alert the clinicians treating people with trastuzumab that they should ask the patients about symptoms of hypothyroidism and should screen the thyroid function of the patients before, during, and after the initiation of trastuzumab. Learning points: Trastuzumab is a humanized MAB used in HER2-positive breast and gastric cancer. Trastuzumab-associated autoimmune thyroid disease (AITD) is rare (incidence rate in an RCT of 0.3%). Manifestations of autoimmune thyroiditis associated with trastuzumab resemble those of hypothyroidism in other clinical contexts, but the presence of goiter is highlighted as a reason for medical evaluation. Biochemically, it is characterized by an increased thyroid-stimulating hormone (TSH) with or without a low FT4/FT3, and sonographically with a pattern of thyroiditis. The treatment consists of levothyroxine, in a dose of 1.6-1.8 µg/kg/day, with re-evaluation of the thyroid function in 4-6 weeks. We report the first case of autoimmune thyroiditis secondary to trastuzumab in Portugal. It is important to evaluate the thyroid function before, during, and after the initiation of this therapeutic agent.

Impact of Selective Serotonin-Reuptake Inhibitors in Hemorrhagic Risk in Anticoagulated Patients Taking Non-Vitamin K Antagonist Anticoagulants: A Systematic Review and Meta-analysis.

BACKGROUND: Studies show an increase in hemorrhagic risk related to selective serotonin-reuptake inhibitors (SSRIs) alone, but also in association with vitamin K antagonists (VKAs). Non-VKA anticoagulants (NOACs) can be a good substitute to VKAs, but the correlation between them and SSRIs is not well studied. Therefore, we conducted a systematic review to evaluate the risk of major bleeding associated with concomitant use of SSRIs and NOACs. METHODS: MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, and PubMed databases were searched, in September 2022, for longitudinal studies evaluating SSRIs' impact on hemorrhagic risk in anticoagulated patients taking NOACs compared with a control group taking non-SSRI medication instead or no antidepressants at all. The outcome of interest was major bleeding. The quality of the included studies was assessed using the ROBINS-I tool. We performed a random-effects meta-analysis to estimate the pooled RRs with 95% confidence intervals (CIs), and heterogeneity was evaluated using the I2 statistic. RESULTS: Eight studies were included in the meta-analysis. From a population of 279,540 anticoagulated patients taking NOACs, the ones taking SSRIs concomitantly were associated with a higher risk of major bleeding (relative risk, 1.33; 95% CI, 1.06-1.66; I2 = 60%). However, the subgroup analysis of cohort studies did not achieve statistical significance (relative risk, 1.05; 95% CI, 0.94-1.66). CONCLUSIONS: The findings show that SSRIs are associated with a greater hemorrhagic risk in patients anticoagulated with NOACs; however, our confidence is reduced because of nonstatistically significant results from more robust studies, as cohort studies.

Síndrome de Cushing ATCH-dependiente durante el embarazo tratado con metirapona / ACTH-dependent Cushing’s syndrome during pregnancy treated with metyrapone

Cushing’s syndrome (CS) rarely occurs during pregnancy due to the influence of the hypercortisolism on the reproductive axis, with only a few cases described. We present a case of a 32 years-old woman diagnosed with ACTH-dependent CS and no clear pituitary lesion on the MRI. She was on ketoconazole when she discovered she was 8-weeks pregnant. Ketoconazole was stopped and a conservative management was decided. At 26 weeks of gestation, the patient developed gestational diabetes and treatment with metyrapone was started. Metyrapone was well tolerated and the pregnancy proceeded without further complications. She gave birth to a male infant, via cesarean section, at 36 weeks, with no apparent teratogenic effects of metyrapone. Many authors consider surgery as the first-choice treatment in pregnant women with CS but there is no consensus on the best management in such patients. Pharmacological treatment with metyrapone may be a safe and effective alternative. (AU)

NGLY1 deficiency-A rare congenital disorder of deglycosylation.

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.

Emotional Wellbeing in Parents of Children on Home Parenteral Nutrition.

OBJECTIVES: Caring for a child on home parenteral nutrition (HPN) is stressful, and its emotional impact not fully appreciated. This study explored the emotional wellbeing and coping styles of parents and children on HPN. METHODS: Questionnaire data were collected for parents of children (0-18 years) on HPN. Children 8 years and older completed the revised children's anxiety and depression scale. Parents completed the Hospital Anxiety and Depression Scale, Paediatric Inventory for Parents (PIP) and brief COPE. RESULTS: A total of 14 children were included, 20 parents (13 females) and 4 children completed the survey. Parents had mean PIP difficulty and frequency score of 117.9 and 124, respectively, higher compared to parents of children with other chronic illness. PIP scores were significantly higher where children were also enterally tube fed (P < 0.05). Thirty-five per cent parents scored above clinical threshold on anxiety subscale of Hospital Anxiety and Depression Scale and 30% in borderline range. On depression subscale 15% scored above clinical threshold range and 15% in borderline range. Mean anxiety and depression scores in parents of children with short bowel syndrome (11.8, 7.8) were significantly higher than those with neuromuscular disease (5.8, 1.6) P < 0.05. Coping styles differed according to health condition and whether child was enterally fed. CONCLUSIONS: There is a significant emotional impact of caring for a child on HPN, assessment and treatment of anxiety, depression, and stress should be a routine part of care. Individual needs of the child and parent need to be taken into account in providing the most appropriate psychological support.

Insulinoma masquerading as neurologic disease - Case report and review of the literature

Insulinomas are the most frequent etiology of hypoglycemia in a non-diabetic patient and the most common functional neuroendocrine tumors of the pancreas, with an annual incidence of about 4 cases per million. The majority of insulinomas are "well-differentiated endocrine tumors" or grade 1 tumors, as defined by World Health Organization. Most tumors are benign, solitary and occur sporadically. However, about 10% are associated with multiple endocrine neoplasia type 1 (MEN-1). Despite the majority being benign tumors, hypoglycemic symptoms caused by the hyperinsulinemia are frequently debilitating. Whipple triad (hypoglycemia, symptoms of hypoglycemia - either adrenergic or neuroglycopenic - and relief of these symptoms after administration of glucose) is usually present and should alert to the diagnosis.After the diagnosis is made, locating the tumor can be challenging because most tumors are small. Nonetheless, locating the tumor is crucial, once the only definite treatment is surgical excision. The majority of patients reach normalization of glucose levels after surgery. Incomplete resection leads to persistent symptoms and although uncommon in sporadic insulinomas, recurrence can be as high as 20% in patients with MEN-1 syndrome

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Evolutionary trends in bacteria isolated from moderate and severe diabetic foot infections in a Portuguese tertiary center.

INTRODUCTION: Diabetic Foot infections (DFI) are a major cause of hospitalization in patients with diabetes. The microbiological study of diabetic ulcers is essential to adequate antibiotic therapy and to minimize the selection of resistant microorganisms. The aim of this study was to characterize and to compare the evolution of isolated microorganisms between the biennium 2010-2011 and 2016-2017, in hospitalized patients with DFI. MATERIAL AND METHODS: Retrospective evaluation of the clinical and analytical data of patients who were admitted due to DFI in 2010-2011 (group 2010/11) and 2016-2017 (group 2016/17). Only the first hospitalization for each patient was included. An adequate descriptive and comparative statistical analysis was performed. RESULTS: There were 274 admissions due to DFI, 151 in 2010/11 and 123 in 2016/17. There was an increase in admissions due to neuroischemic DFI (51.0% in 2010/11 to 61.8% in 2016/17, p = 0.048). Staphylococcus aureus (SA) was the most common isolate in 2010/11 (26.7%). In 2016/17 most cultures were mixed polymicrobial and isolation of Enterobacteriaceae and Pseudomonas aeruginosa increased from 2010/11 to 2016/17 (15.9% to 30.6%, p = 0.001, and 9.1% to 13.7%, p = 0.048, respectively). CONCLUSION: There was an increase in the prevalence of neuroischemic DFU. The Enterobacteriaceae family replaced SA as the most prevalent pathogen in DFI, with an increase in the isolation of gram-negative microorganisms and mixed polymicrobial cultures. Chronic neuroischemic infected ulcers usually present distinct bacterial isolates; knowledge about the most common agents is warranted in order to better select empiric antibiotic therapy.

Impact of overweight and obesity on pregnancy outcomes in women with gestational diabetes - results from a retrospective multicenter study

ABSTRACT Objective The aim of this study was to evaluate the impact of pre-pregnancy body mass index (BMI) on pregnancy outcomes in women with gestational diabetes (GD). Subjects and methods Retrospective multicenter study using data from the Portuguese National Register. We included women with GD with a singleton pregnancy. GD diagnosis was according to the International Association of the Diabetes and Pregnancy Study Group criteria. Women were divided into groups according to their pre-pregnancy BMI: < 18.5 kg/m2 (underweight), ≥ 18.5 and < 25.0 kg/m2 (normal weight), ≥ 25 and < 30 kg/m2 (overweight) and ≥ 30 kg/m2 (obese). Results We included 3,103 pregnant women with GD, 29.6% (n = 918) were overweight and 27.3% (n = 846) were obese. Compared to normal weight, the overweight and obese groups had a higher percentage of gestational hypertension (4.0% and 8.5% vs. 2.1%), cesarean delivery (32.8% and 41.3% vs. 27.9%), macrosomia (3.9% and 6.7% vs. 2.4%), and large for gestational age (LGA) newborns (8.3% and 13.5% vs. 6.0%). Obesity increased the risk of gestational hypertension (OR 4.5, p < 0.001), preeclampsia (OR 1.9, p = 0.034), cesarean delivery (OR 2.0, p < 0.001), macrosomia (OR 3.1, p < 0.001) and LGA (OR 2.3, p < 0.001). Conclusion In pregnant women with GD, pregnancy complications increase with pre-pregnancy BMI. In obese women, appropriate diet and counseling prior to gestation and more aggressive medical intervention during pregnancy are needed in order to prevent macrosomic and LGA newborns and to reduce maternal complications.

Impact of overweight and obesity on pregnancy outcomes in women with gestational diabetes - results from a retrospective multicenter study.

Objective The aim of this study was to evaluate the impact of pre-pregnancy body mass index (BMI) on pregnancy outcomes in women with gestational diabetes (GD). Subjects and methods Retrospective multicenter study using data from the Portuguese National Register. We included women with GD with a singleton pregnancy. GD diagnosis was according to the International Association of the Diabetes and Pregnancy Study Group criteria. Women were divided into groups according to their pre-pregnancy BMI: < 18.5 kg/m2 (underweight), ≥ 18.5 and < 25.0 kg/m2 (normal weight), ≥ 25 and < 30 kg/m2 (overweight) and ≥ 30 kg/m2 (obese). Results We included 3,103 pregnant women with GD, 29.6% (n = 918) were overweight and 27.3% (n = 846) were obese. Compared to normal weight, the overweight and obese groups had a higher percentage of gestational hypertension (4.0% and 8.5% vs. 2.1%), cesarean delivery (32.8% and 41.3% vs. 27.9%), macrosomia (3.9% and 6.7% vs. 2.4%), and large for gestational age (LGA) newborns (8.3% and 13.5% vs. 6.0%). Obesity increased the risk of gestational hypertension (OR 4.5, p < 0.001), preeclampsia (OR 1.9, p = 0.034), cesarean delivery (OR 2.0, p < 0.001), macrosomia (OR 3.1, p < 0.001) and LGA (OR 2.3, p < 0.001). Conclusion In pregnant women with GD, pregnancy complications increase with pre-pregnancy BMI. In obese women, appropriate diet and counseling prior to gestation and more aggressive medical intervention during pregnancy are needed in order to prevent macrosomic and LGA newborns and to reduce maternal complications.

Nivolumab-induced hypothyroidism followed by isolated ACTH deficiency.

Cancer immunotherapy has been used in several malignancies with clinical benefit. Despite the clinical success, immune-related adverse events are frequent and endocrinopathies can be particularly severe. We report a 55-year-old male patient with stage IV pulmonary carcinoma treated with nivolumab who presented with thyroid dysfunction after the sixth administration of the drug. One year after thyroid dysfunction, the patient complained of severe fatigue, asthenia and weight loss. Laboratory testing showed low morning cortisol with undetected adrenocorticotropic hormone; other pituitary hormones were normal and MRI showed homogeneous enhancement of the pituitary gland and no space-occupying lesions. The diagnosis of nivolumab-induced hypophysitis was made and replacement treatment with hydrocortisone was started with clinical improvement. This case demonstrates that patients under immunotherapy are at risk for a large spectrum of endocrine dysfunctions that may worsen their prognosis. Close monitoring of these patients is warranted.

Graves' disease complicated by fetal goitrous hypothyroidism treated with intra-amniotic administration of levothyroxine.

Fetal goitrous hypothyroidism is a rare entity and is caused mainly by maternal treatment of Graves' disease (GD). We report a case of a 22-year-old woman referred at 12 weeks of gestation due to hyperthyroidism subsequent to recently diagnosed GD. She started treatment with propylthiouracil and, at 21 weeks of gestation, fetal goitre was detected. A cordocentesis confirmed the diagnosis of fetal goitrous hypothyroidism, and intra-amniotic administration of levothyroxine (LT4) was performed and repeated through the pregnancy due to maintenance of fetal goitre. The pregnancy proceeded without further complications and a healthy female infant was born at 37 weeks of gestation, with visible goitre and thyroid function within the normal range at birth. Although there is no consensus on the optimal dose, the number of injections and the interval between them, intra-amniotic LT4 administration is recommended once fetal goitrous hypothyroidism is suspected, in order to prevent long-term complications of fetal hypothyroidism.

Validation of a Next-Generation Sequencing Pipeline for the Molecular Diagnosis of Multiple Inherited Cancer Predisposing Syndromes.

Despite the growing knowledge of the genetic background behind the cancers that occur in a context of hereditary predisposition, personal or family cancer history may not be clear enough to support directional gene testing. Defined targeted next-generation sequencing gene panels allow identification of the causative disease mutations of multigene syndromes and differential diagnosis for syndromes with phenotypically overlapping characteristics. Herein, we established a next-generation sequencing analysis pipeline for the molecular diagnosis of multiple inherited cancer predisposing syndromes using the commercially available target sequencing panel TruSight Cancer. To establish the analysis pipeline, we included 22 control samples with deleterious mutations covering all genes currently analyzed at our institution by standard Sanger sequencing. We tested the pipeline using 51 samples from patients with a clinical diagnosis of neurofibromatosis type 1 (NF1), 10 of which without previous molecular characterization of the causative NF1 mutations. We propose a thoroughly validated analysis pipeline that combines Isaac Enrichment, Burrows-Wheeler Aligner Enrichment, and NextGENe for the alignment and variant calling, and GeneticistAssistant for variant annotation and prioritization. This pipeline allowed the identification of disease-causing mutations in all 73 patients, including a large duplication of 37 bp in NF1. We show that high sensitivity and specificity can be achieved by using multiple bioinformatic tools for alignment and variant calling and careful variant filtering, having in mind the clinical question.

Infections on the rise: Raoultella spp., clinical and microbiological findings from a retrospective study, 2010-2014.

We performed a retrospective analysis of clinical and laboratory data over 5 years in a tertiary centre to assess clinical and microbiological characteristics of patients with Raoultella spp. infection. Raoultella spp. were deemed responsible for clinical infections in 57 patients (R. planticola, n = 32 and R. ornithinolytica, n = 25). The most prevalent diagnoses for R. planticola were cystitis (50%; n = 16) followed by bacteraemia and pneumonia (9.4%; n = 3); for R. ornithinolytica, cystitis (36%; n = 9) followed by pneumonia (24%; n = 6). Immunodeficiency was present in 18 patients (56.3%) with R. planticola and in 16 patients (64%) with R. ornithinolytica infection. Of these, 55.6% and 37.5% had diabetes and 27.8% and 18.% were solid organ transplant recipients, respectively. All isolates were sensitive to third-generation cephalosporins, fluoroquinolones and aminoglycosides. Mortality of infections with R. planticola (n = 5; 15.6%) was higher than for R. ornithinolytica (n = 2; 8.0%), but the difference was not statistically significant.

The unexpected finding of a splenic infarction in a patient with infectious mononucleosis due to Epstein-Barr virus.

The authors present a case of a 24-year-old man with infectious mononucleosis (IM) due to Epstein-Barr virus (EBV). Among his symptoms, he reported abdominal pain in the upper left quadrant. An abdominal ultrasound and CT revealed an extensive splenic infarction. During the acute stage of this disease, the thrombophilic screening revealed reduced free protein S and elevated factor VIII, with normalisation on re-evaluation 6 weeks later. Splenic infarction is a very rare complication of IM due to EBV but should be considered in patients presenting abdominal pain. A hypercoagulability state should be investigated. To our knowledge, this is the first described case of a splenic infarction in a patient with IM due to EBV associated with a transient reduction of protein S and elevation of factor VIII. Thus, this work promotes the importance of including these factors in the thrombophilic screening conducted during the investigation of similar cases.

Streptococcus gallolyticus: a single bacteria, two different conditions.

The authors describe the case of a 48-year-old woman presenting with fever, joint pain and migratory skin lesions. She had no other symptoms or medical history. After an extensive and inconclusive work up, she was admitted to the hospital for further study. This patient was ultimately found to have Streptococcus gallolyticus subsp gallolyticus bacteraemia. This finding led to the diagnosis of mitral valve infective endocarditis related to an underlying rectum adenocarcinoma. This article points out diagnostic difficulties related to an unusual presentation of the underlying disease. Furthermore, the authors reinforce the need of keeping a high level of suspicion and a systematic approach in every case of fever of unknown origin. This case highlights the importance of performing a colonoscopy in the event of S. gallolyticus subsp gallolyticus bacteraemia, as it may provide an opportunity for detecting colonic lesions at an earlier stage.

Rupturas na aliança terapêutica e expressão verbal de necessidades do cliente: um estudo de caso / Psychotherapeutic alliance ruptures and verbal expression of client's needs: a case study

Apresentamos um estudo de caso cujo objectivo foi explorar a associação entre as rupturas na aliança terapêutica e a expressão verbal de necessidades do cliente em psicoterapia. Foi analisado um caso de insucesso de um cliente diagnosticado com Transtorno de Pânico com Agorafobia, através do Rupture Resolution Rating System (3R's) e do Sistema de Observação de Responsividade Terapêutica Os dados resultantes da aplicação dos dois sistemas de observação foram analisados com o software de análise de séries temporais SMA. Os resultados indicam que um aumento da Expressão Verbal de Necessidades numa sessão está associada a uma diminuição dos marcadores de ruptura após três e quatro sessões e um aumento dos marcadores de rupturas numa sessão está associado a um aumento da EVN após quatro sessões. Esta associação foi mais evidente entre as rupturas de confronto, particularmente do marco de insatisfação com as actividades da terapia, e a expressão de necessidades directamente relacionadas com a terapia.(AU)

We present a case study whose main goal was to explore the relationship between therapeutic alliance's ruptures and the client's verbal expression of needs in psychotherapy. We intensively analyzed an unsuccessful case of a client with Panic Disorder with Agoraphobia. The sessions were analyzed using the Ruptures Resolution Rating System (3R's) and the Sistema de Observação de Responsividade Terapêutica . The results indicate that an increase in the Verbal Expression of Needs (EVN) is associated with a decrease of the ruptures three and four sessions later and that an increase in ruptures is associated with an increase of EVN four sessions later. There was a more clear association between the confrontation ruptures, particularly the expression of dissatisfaction about therapeutic activities, and a specific type of EVN:the client's expression of direct requests related to therapy.(AU)

Rupturas na aliança terapêutica e expressão verbal de necessidades do cliente: um estudo de caso / Psychotherapeutic alliance ruptures and verbal expression of client's needs: a case study

Apresentamos um estudo de caso cujo objectivo foi explorar a associação entre as rupturas na aliança terapêutica e a expressão verbal de necessidades do cliente em psicoterapia. Foi analisado um caso de insucesso de um cliente diagnosticado com Transtorno de Pânico com Agorafobia, através do Rupture Resolution Rating System (3R's) e do Sistema de Observação de Responsividade Terapêutica Os dados resultantes da aplicação dos dois sistemas de observação foram analisados com o software de análise de séries temporais SMA. Os resultados indicam que um aumento da Expressão Verbal de Necessidades numa sessão está associada a uma diminuição dos marcadores de ruptura após três e quatro sessões e um aumento dos marcadores de rupturas numa sessão está associado a um aumento da EVN após quatro sessões. Esta associação foi mais evidente entre as rupturas de confronto, particularmente do marco de insatisfação com as actividades da terapia, e a expressão de necessidades directamente relacionadas com a terapia.

We present a case study whose main goal was to explore the relationship between therapeutic alliance's ruptures and the client's verbal expression of needs in psychotherapy. We intensively analyzed an unsuccessful case of a client with Panic Disorder with Agoraphobia. The sessions were analyzed using the Ruptures Resolution Rating System (3R's) and the Sistema de Observação de Responsividade Terapêutica . The results indicate that an increase in the Verbal Expression of Needs (EVN) is associated with a decrease of the ruptures three and four sessions later and that an increase in ruptures is associated with an increase of EVN four sessions later. There was a more clear association between the confrontation ruptures, particularly the expression of dissatisfaction about therapeutic activities, and a specific type of EVN:the client's expression of direct requests related to therapy.