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The criteria for clinical diagnosis of neurofibromatosis type 1 (NF1) are not sensitive in young children. Recognition is easier when one of their parents has been diagnosed with this condition, and the causal mutation is known. We present a case of a girl with isolated café-au-lait spots, whose father was diagnosed with NF1. However, both were found to carry different de novo mutations in the NF1 gene. This possibility has significant implications for the diagnostic process and genetic counseling., (© 2024 The Author(s). Pediatric Dermatology published by Wiley Periodicals LLC.)

Aims: Limited data exist on low-density lipoprotein-cholesterol (LDL-C) level variability or long-term persistence with the monoclonal antibody evolocumab in routine clinical practice. HEYMANS (NCT02770131) is the first multi-country, multicenter, observational study of European patients initiating evolocumab as part of their routine clinical management, based on local reimbursement criteria (overall data recently published). The aim of this analysis is to describe clinical characteristics, baseline and changes in LDL-C levels, treatment patterns and persistence to evolocumab over 30 months in the Spanish cohort using data from the HEYMANS Registry., Methods: HEYMANS was a prospective study of adult patients (≥18 years) who received at least one dose of evolocumab. A total of 1951 patients were enrolled from 12 countries and were followed up for 30 months after evolocumab initiation. Data were collected for 6 months before evolocumab initiation and up to 30 months thereafter. The Spanish cohort included patients who started evolocumab in routine clinical practice from March 2016 to September 2019. Demographic and clinical characteristics, lipid-lowering therapies (LLT), and lipid levels were collected., Results: In total, 201 patients were included in the Spanish cohort. Median follow-up (Q1-Q3) was 30.0 (12-30) months. A total of 61.7% of patients were men and the mean (standard deviation) age was 59.5 (10.8) years. Most patients (68.7%) had experienced a prior cardiovascular event, 45.3% had coronary artery disease or stable angina, and 60.2% had a diagnosis of familial hypercholesterolemia. Overall, 57.7% of patients were receiving treatment with statins, most of them with high-intensity statins (85.3%); 45.8% of patients were intolerant to statins, and 26.4% of patients did not receive any LLT. At baseline, median (Q1-Q3) LDL-C levels were 151 (123-197) mg/dL. After 3 months of treatment, baseline LDL-C decreased by 66% to a median of 50 (30-83) mg/dL and these levels were maintained over time, with a median LDL-C of 55 (40-99) mg/dL at 30 months. At months 10-12 of treatment, LDL-C levels<55mg/dL were achieved by 56.3% of patients. LDL-C levels<70mg/dL were achieved by 70.1% of patients, and a lowering of LDL-C levels ≥50% was achieved by 76.8% of patients. The percentage of patients on evolocumab treatment was 95% at 12 months and 93% at 30 months., Conclusions: In the Spanish cohort in routine clinical practice, evolocumab therapy provided a reduction in LDL-C levels consistent with that reported in previous clinical trials, which was sustained during 30 months of follow-up. Treatment with evolocumab was started at LDL-C levels 50% higher than those recommended by The Spanish Society of Arteriosclerosis and the Therapeutic Positioning Report. The probability of achieving the 2019 ESC/EAS LDL-C goals would improve with combination therapy and also with a lower LDL-C threshold when starting evolocumab. Persistence to evolocumab remained high during follow-up, with a very low percentage of discontinuation (5% at 12 months; 7% at 30 months)., (Copyright © 2023 The Authors. Publicado por Elsevier España, S.L.U. All rights reserved.)

Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a very rare hereditary disorder characterized by cutaneous leiomyomas (CLMs), uterine leiomyomas (ULMs), renal cysts (RCys) and renal cell cancers (RCCs). We aimed to describe the genetics, clinical features and potential genotype-phenotype associations in the largest cohort of fumarate hydratase enzyme mutation carriers known from Spain using a multicentre, retrospective study of individuals with a genetic or clinical diagnosis of HLRCC. We collected clinical information from medical records, analysed genetic variants and looked for genotype-phenotype associations. Analyses were performed using R 3.6.0. software. We included 197 individuals: 74 index cases and 123 relatives. CLMs were diagnosed in 65% of patients, ULMs in 90% of women, RCys in 37% and RCC in 10.9%. Twenty-seven different pathogenic variants were detected, 12 (44%) of them not reported previously. Patients with missense pathogenic variants showed higher frequencies of CLMs, ULMs and RCys, than those with loss-of-function variants ( p = 0.0380, p = 0.0015 and p = 0.024, respectively). This is the first report of patients with HLRCC from Spain. The frequency of RCCs was lower than those reported in the previously published series. Individuals with missense pathogenic variants had higher frequencies of CLMs, ULMs and RCys.

Currently there is evidence on hypertriglyceridaemia as an independent risk factor of atherosclerosis. Chylomicronaemia associated with very high concentration of triglycerides may cause severe and recurrent acute pancreatitis. The cause of most cases is a combination of a polygenetic basis with some lifestyles and pathological conditions. Some rare and familial chylomicronaemias are mendelian diseases with an autosomal recessive pattern. On the other hand, plasma triglycerides have considerable biological variability and usually descend with non-pharmacological interventions alone. In some cases, drugs are also required for their control, but their impact on vascular risk reduction or pancreatitis prevention is more controversial. The recent advances in knowledge of molecular lipid metabolism and pharmacological technologies are resulting in the development of new therapeutic strategies, which can be applied to patients with refractory hypertrigliceridaemia. The challenge may be how the health systems can cover its high costs., (Copyright © 2019 Elsevier España, S.L.U. All rights reserved.)

Background: Constitutional MLH1 epimutations are characterised by monoallelic methylation of the MLH1 promoter throughout normal tissues, accompanied by allele-specific silencing. The mechanism underlying primary MLH1 epimutations is currently unknown. The aim of this study was to perform an in-depth characterisation of constitutional MLH1 epimutations targeting the aberrantly methylated region around MLH1 and other genomic loci., Methods: Twelve MLH1 epimutation carriers, 61 Lynch syndrome patients, and 41 healthy controls, were analysed by Infinium 450 K array. Targeted molecular techniques were used to characterise the MLH1 epimutation carriers and their inheritance pattern., Results: No nucleotide or structural variants were identified in-cis on the epimutated allele in 10 carriers, in which inter-generational methylation erasure was demonstrated in two, suggesting primary type of epimutation. CNVs outside the MLH1 locus were found in two cases. EPM2AIP1-MLH1 CpG island was identified as the sole differentially methylated region in MLH1 epimutation carriers compared to controls., Conclusion: Primary constitutional MLH1 epimutations arise as a focal epigenetic event at the EPM2AIP1-MLH1 CpG island in the absence of cis-acting genetic variants. Further molecular characterisation is needed to elucidate the mechanistic basis of MLH1 epimutations and their heritability/reversibility.

Extremely low LDL-cholesterol concentrations are very unusual and generally related with comorbidities accompanying malnutrition. Less frequently low LDL-cholesterol levels result from mutations in the APOB, PCSK9, ANGPTL3, SAR1B and MTTP genes (primary hypobetalipoproteinemia). We investigated three patients with plasma LDL-cholesterol levels below the fifth percentile of the Spanish population. We recorded data on demographic and anthropometric characteristics, life style habits, physical examination, liver ultrasound and lipid and lipoprotein levels, in the probands and their first-degree relatives. Secondary causes of hypocholesterolemia were ruled out by clinical study, complementary tests and follow-up. The APOB, MTTP and SAR1B genes were sequenced. Patients were found to be heterozygotes for point mutations located in the exon 26 of the APOB gene. One patient, with fatty liver, carried a previously described mutation (c.7600C>T) (Arg2507X), causing the formation of truncated Apo B-55.25. The other two mutations producing truncations are new. One asymptomatic patient carried the Arg3672X (Apo B-80.93) and the other with fatty liver and steatorrhea carried the Ser2184fsVal2193X (Apo B-48.32). Our study reinforces the concept that in the heterozygous carriers of truncated Apo Bs, the clinical manifestations of FHBL are dependent on the size of the truncations., (© 2013 Elsevier B.V. All rights reserved.)

Background: The aim of the present study was to evaluate the diagnostic value of the tumour markers carcinoembryonic antigen (CEA), carbohydrate antigens CA 125, CA 15.3, CA 19.9 and tumor-associated glycoprotein 72 (TAG 72) in the pleural fluid (PF) of patients with pleural effusions of different etiologies., Patients and Methods: One hundred and fifty-five patients with pleural effusions (40 malignant, 84 benign and 31 paraneoplastic) were studied prospectively. The concentration of the tumour markers in serum and PF were measured by magnetic particle enzyme immunoassay. The PF to serum (PF/S) concentration ratios were calculated., Results: The concentrations of CEA, CA 15.3, CA 19.9 and TAG 72 in PF and the PF/serum ratios were significantly higher in effusions of malignant and paraneoplastic origin than in those of benign origin. The receiver operating characteristic (ROC) curves were calculated for each marker and the diagnostic cut-off point was selected as the value that offered a specificity of 100% (CEA: 6.5 ng/ml; CA 15.3:62.4 IU/l; TAG 72:10.9 IU/l). CEA presented the greatest sensitivity [45% in the malignant group, 38.7% in the paraneoplastic group, and 41.4% in the pooled group (combined malignant and paraneoplastic)]. TAG 72 presented the largest area under the curve (0.89 in the malignant group and 0.80 in the pooled group). The diagnostic efficacy of the PF/S ratios was not better than measurement of the tumour markers in pleural fluid. The highest diagnostic accuracy for the diagnosis of malignant pleural effusions was achieved by grouping the markers in a panel comprising CEA, CA 15.3 and TAG 72; this showed a sensitivity of 75% and a negative predictive value of 79.1% . In the subgroup of patients with negative cytology, the sensitivity was 41.2% for CEA, 35.5% for CA 15.3 and 33.3% for TAG 72. The combination of these three markers achieved a sensitivity of 84.6%., Conclusion: The combined measurement of CEA, CA 15.3 and TAG 72 in pleural fluid is a useful complementary test in the differential diagnosis of pleural effusions of malignant origin.

Background: Malabsorptive techniques to treat morbid obesity have been followed by alterations in phosphocalcic metabolism. Knowledge of the preoperative situation is important to assess the influence of these techniques on phosphocalcic metabolism and to consider treatments for these alterations., Methods: 61 consecutive morbidly obese patients (50 women, 11 men, age 19 to 63 years) having had biliopancreatic diversion (BPD) were studied in a prospective manner. Preoperative and postoperative levels of calcium, phosphorus, 25-hydroxyvitamin D, tartrate resistant acid phosphate, plasma parathormone (PTH), tubular absorption of phosphate, and urinary calcium and pyridinolines were analyzed, as well as the potential risk factors for their alterations. Follow-up of all patients was a minimum of 4 years., Results: Before BPD, 42.3% of patients presented an increase in PTH and 54% a decrease in the 25-OH vitamin D, but the values of calcium and plasma phosphorus maintained at normal level. 81.8% of the patients with an increase in the PTH maintained high levels after BPD, while 60% of those with a normal preoperative PTH also presented hyperparathyroidism 4 years after the intervention. A correlation between the levels of plasma PTH and body mass index was not found., Conclusion: Morbid obesity is accompanied by a high percentage of hyperparathyroidism. BPD produces malabsorption of vitamin D during the first years, favoring the persistence or appearance of hyperparathyroidism. It is important to recognize and treat the secondary hyperparathyroidism. The postoperative period could necessitate more energetic interventions to get more efficient control of the phosphocalcic metabolism.

Introduction: The prevalence of palpable thyroid nodules in the general population is 4%-7%. Although most are benign, 5% are carcinomas. This study aimed to assess the efficacy of fine needle aspiration biopsy (FNAB) of thyroid nodules to diagnose malignancy and know the benefit of repeating the FNAB in the same nodule., Patients and Methods: A total of 510 patients (431 women and 79 men; mean age [standard deviation]: 47.6 [14.3] years) with surgery due to thyroid nodular condition between 1989 and 2002 and who had at least one FNAB prior to the surgery were studied., Results: The first FNAB was benign in 312 patients (61.2%), malignant in 38 (7.5%), suspicious or indeterminate in 97 (19%) and insufficient in 63 (12.4%). Sensitivity and specificity in the first FNAB for malignancy diagnosis was 76% and 84%, respectively. Successive FNABs had a moderate concordance and significance. However, repeating the puncture did not improve diagnostic performance, since sensitive increased (84%), but specificity worsened (79%) and the area under the ROC curve was similar. In the group with suspicious or indeterminate FNAB, histology was benign in 70% and malignant in 30%., Conclusions: FNAB sensitivity and specificity for diagnosis of malignancy in thyroid nodules are high. Repetition of puncture on the same nodule does not improve diagnostic performance of the cytology. Among patients with suspicious FNAB, there is a high proportion of malignancy, which makes surgery necessary in these cases.

Objectives: To analyze the incidence, clinical and histopathological manifestations, surgical complications, and prognostic factors of thyroid cancer in the east Madrid population., Patients and Methods: Retrospective analysis of 141 consecutive diagnosed of thyroid cancer in our area between 1985 and 2001. Median follow-up was 4,5 years., Results: The annual incidence rate was 4.74/100,000 inhabitants and the female:male proportion 3.5:1. The average age of patients at diagnosis was 44.5 years and nodular goiter was the principal type of clinical presentation (74.5%). The most frequent histological variant was papillary thyroid carcinoma (69%). Total thyroidectomy was carried out in 86% patients. 9.6% patients suffered permanent hypoparathyroidism and 3.3% paralysis of recurrent laryngeal nerve. Radioactive iodine ablation of remaining thyroid was carried out in 91 patients. Residual disease or local recurrence was observed on follow-up in 21% of patients, and metastasis at a distant site in 9%. 7.9% died along follow-up. The principal prognostic factors for metastasis or death were age, histological type, tumor size, local invasion and existence of metastasis at the time of diagnosis., Conclusions: The incidence of thyroid cancer in our population was high, especially in women. Although the proportion of postsurgical complications was elevated, global prognosis is good and some factors related to it have been identified. Increase of thyroglobulin plasma level at follow-up is a good recurrence indicator of the disease, especially with regard to distant metastases.

Background: Lipoprotein (a) is an independent risk factor for coronary heart disease, particularly the premature form. However, differences in its effect have been observed between men and women and in different populations., Subjects and Methods: Lipid and non-lipid risk factors were compared (univariate and multivariate analyses) between a group of patients with myocardial infarction aged less than 65 years (n = 33) and those in their siblings (n = 32) and an unrelated healthy control group (n = 45) of the same gender., Results: No differences were observed between male patients and their siblings. Differences were indeed observed when patients when compared with controls regarding HDL cholesterol (p = 0.001) and lipoprotein(a) (p = 0.002) serum concentrations. Female patients also had lower serum concentrations of HDL cholesterol than their siblings and controls, but non significant differences were observed for lipoprotein (a). The analysis of lipoprotein (a), categorized with respect to the 90th percentile of controls for each gender, showed a significant association with coronary heart disease only for males: crude odds ratio (OR) compared with controls 10.7 (95% CI: 2.1-54.9) and adjusted of 9.9 (95% CI: 1.6-60.7). The strength of this association was smaller and non-significant in women: crude OR 6,4 (95% CI: 0.8-51.8) and adjusted of 3.09 (95% CI: 0.3-47.2)., Conclusions: Lipoprotein (a) concentrations are similar in siblings and increased concentrations in our population are more strongly and clearly association with coronary heart disease in men.

Background: Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) is a disorder diagnosed with low frequency, that produces a very prolonged and recurrent fever with other symptoms and analytical markers of inflammation. Its origin seems to be hereditary with a recessive autosomic pattern, but its pathogenic mechanisms are unclear. The aim of this study is to analyse the clinical characteristics and serum levels of immunoglobulins a Spanish family with HIDS., Methods: We describe a young woman diagnosed with HIDS and investigate the other memberships of her family (parents and 5 brothers) by clinical interview, physical examination, hematological and biochemical analyses and measurements of IgG, IgA, IgM, IgE, IgD and the kappa/lambda ratio of light chains. Moreover, we also determine the IgD in a control group of 35 healthy blood donors., Results: One male brother of the index case also showed a clinical picture of HIDS. The serum IgD levels were increased (above 100 U/ml) in both and in other two sisters without symptoms and were normal in the rest of the family. With only one exception, all individuals of the control group showed a normal IgD level and this was not associated with sex or age. The other immunoglobulins were normal in the family. In spite of the different treatments tested in the index case, only glucocorticoids aborted her fever attacks., Conclusions: In HIDS the clinical picture and the high IgD levels are both transmitted with a recessive autosomic pattern, but these are not necessarily associated in the same memberships of the family. Its diagnosis is difficult and there is not effective and long-term safe treatment.

Eight type I thyroplasties were performed. All the patients had a breathy voice related with unilateral vocal cord paralysis. Several causes were involved. All 8 patients achieved good glottic closure and the free edges of the vocal cords mi closed uniformly. Acoustic parameters were studied using Dr. Speech version 2.0 for Windows. The SPSS program was used for statistical analysis. The study showed significant improvement in maximum phonation time, shimmer, and normalized noise energy. Modifications in the surgical technique are discussed.

A 52 year old woman with CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal hypomotility and telangiectasia) and visceral involvement of the kidneys, lungs and liver is presented. The hepatic implication was a focal nodular hyperplasia of the liver which is a component not frequently recognized. Another 4 cases of this syndrome, associated to different forms of scleroderma, were described previously. Because of the way in which this case developed, this disease should be suspected when alkaline phosphatase and gamma-glutamyltranspeptidase levels are elevated. We comment on the utility of the laparoscopy and liver biopsy in diagnosing the diseased and the situation found. Finally, we discuss the pathogenic implications of the disease with scleroderma, owing to the vascular mechanism.