Uncovering genetic causes of hypophosphatemia.

BACKGROUND: Chronic hypophosphatemia can result from a variety of acquired disorders, such as malnutrition, intestinal malabsorption, hyperparathyroidism, vitamin D deficiency, excess alcohol intake, some drugs, or organ transplantation. Genetic disorders can be a cause of persistent hypophosphatemia, although they are less recognized. We aimed to better understand the prevalence of genetic hypophosphatemia in the population. METHODS: By combining retrospective and prospective strategies, we searched the laboratory database of 815,828 phosphorus analyses and included patients 17-55 years old with low serum phosphorus. We reviewed the charts of 1287 outpatients with at least 1 phosphorus result ≤2.2 mg/dL. After ruling out clear secondary causes, 109 patients underwent further clinical and analytical studies. Among them, we confirmed hypophosphatemia in 39 patients. After excluding other evident secondary causes, such as primary hyperparathyroidism and vitamin D deficiency, we performed a molecular analysis in 42 patients by sequencing the exonic and flanking intronic regions of a panel of genes related to rickets or hypophosphatemia (CLCN5, CYP27B1, dentin matrix acidic phosphoprotein 1, ENPP1, FAM20C, FGFR1, FGF23, GNAS, PHEX, SLC34A3, and VDR). RESULTS: We identified 14 index patients with hypophosphatemia and variants in genes related to phosphate metabolism. The phenotype of most patients was mild, but two patients with X-linked hypophosphatemia (XLH) due to novel PHEX mutations had marked skeletal abnormalities. CONCLUSION: Genetic causes should be considered in children, but also in adult patients with hypophosphatemia of unknown origin. Our data are consistent with the conception that XLH is the most common cause of genetic hypophosphatemia with an overt musculoskeletal phenotype.

Effect of prenatal exposure to organophosphates and pyrethroid pesticides on neonatal anthropometric measures and gestational age.

Several studies have examined the association between prenatal exposure to organophosphate and pyrethroid pesticides and their impact on foetal growth and newborn anthropometry; however, the available evidence is limited and inconclusive. This study examined whether prenatal organophosphate and pyrethroid pesticide exposure was associated with anthropometric measures at birth (weight, length, head circumference), ponderal index, gestational age, and prematurity in 537 mother-child pairs. These were randomly selected from the 800 pairs participating in the prospective birth cohort GENEIDA (Genetics, early life environmental exposures and infant development in Andalusia). Six non-specific organophosphate metabolites (dialkylphosphates, DAPs), one metabolite relatively specific to chlorpyrifos (3,5,6-trichloro-2-pyridinol, TCPy) and a common metabolite to several pyrethroids (3-phenoxybenzoic acid, 3-PBA) were measured in maternal urine from the 1st and 3rd pregnancy trimesters. Information on anthropometric measures at birth, gestational age and prematurity was retrieved from medical records. The sum on a molar basis of DAPs with methyl (Æ©DMs) and ethyl (Æ©DEs) moieties and the sum of the 6 DAPs metabolites (Æ©DAPs) was calculated for both trimesters of pregnancy. High urinary levels of dimethyl phosphate (DMP) during the 3rd trimester were associated with a decrease in birth weight (ß = -0.24; 95% CI: 0.41; -0.06) and birth length (ß = -0.20; 95% CI: 0.41; 0.02). Likewise, ΣDMs during 3rd trimester were near-significantly associated with decreased birth weight (ß = -0.18; 95% CI: 0.37; 0.01). In turn, increased urinary TCPy during 1st trimester was associated with a decreased head circumference (ß = -0.31; 95% CI: 0.57; -0.06). Finally, an increase in 3-PBA in the 1st trimester was associated with a decreased gestational age (ß = -0.36 95% CI: 0.65-0.08), whereas increased 3-PBA at 1st and 3rd trimester was associated with prematurity. These results indicate that prenatal exposure to organophosphate and pyrethroid insecticides could affect normal foetal growth, shorten gestational age and alter anthropometric measures at birth.

[High frequency of dyslipidemia in children and adolescents with Down Syndrome]. / Alta frecuencia de dislipidemias en niños y adolescentes con Síndrome de Down.

Down Syndrome (DS) shows an increased risk of chronic diseases, associated to higher morbidity and mortality for cardiovascular disease. Some studies have shown a worse lipid profile in children with DS, however, until now there is no recommendation for screening for dyslipidemia in these subjects. OBJECTIVE: To describe the frequency of dyslipidemia in a population of Chilean children and adolescents with DS. PATIENTS AND METHOD: Retrospective study, including patients with DS, aged 2 to 18 years, who participated in a special health care program for people with DS in Health Net UC CHRISTUS, between 2007 and 2015. Patients who had a lipid profile between their routine laboratory tests were included. Clinical characteristics, relevant comorbidities, malformations, medications, nutritional status and pubertal development were obtained from medical records. Diagnosis of dyslipidemia was considered according to the criteria of the NHLBI 2011. RESULTS: The medical records of 218 children with DS were revised, 58,3% had some type of dyslipidemia. The most frequent single dyslipidemias were low HDL Chol (15,1%) and hypertriglyceridemia (12,8%). Atherogenic dyslipidemia (low HDL plus hypertriglyceridemia) was the most frequent combined dyslipidemia (13,3%). The occurrence of atherogenic dyslipidemia was not associated with overnutrition and obesity. CONCLUSIONS: A high frequency of dyslipidemia was found in Chilean children and adolescents with DS. Our results make us suggest that lipid profile should be performed early in all patients with DS, independent of the presence of risk factors for dyslipidemia.

Rs219780 SNP of Claudin 14 Gene is not Related to Clinical Expression in Primary Hyperparathyroidism.

BACKGROUND: The CLDN14 gene encodes a protein involved in the regulation of paracellular permeability or ion transport at epithelial tight junctions as in the nephron. The C allele of the rs219780 SNP (single nucleotide polymorphism) of CLDN14 has been associated with renal lithiasis, high levels of parathormone (PTH), and with low bone mineral density (BMD) in healthy women. Our aim is to study the relationship between rs219780 SNP of CLDN14 and renal lithiasis, fractures, and BMD in patients with primary hyperparathyroidism (PHPT). METHODS: We enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analysed anthropometric data, history of fractures or kidney stones, biochemical parameters including markers for bone remodelling, abdominal ultrasound, and BMD and genotyping for the rs219780 SNP of CLDN14. RESULTS: We did not find any difference in the frequency of fractures or renal lithiasis between the genotype groups in PHPT patients. Moreover, we did not find any relationship between the T or C alleles and BMD or biochemical parameters. CONCLUSIONS: rs219780 SNP of CLDN14 does not appear to be a risk factor for the development of PHPT nor does it seem to influence the clinical expression of PHPT.

Late-onset subcutaneous scalp calcifications in a patient with pseudo-pseudohypoparathyroidism.

Ectopic calcifications and even bone formation have been linked to GNAS gene mutations. A 51-year-old Caucasian female had been diagnosed of pseudo-pseudohypoparathyroidism (PPHP) in 1989. She has always had normal serum parathyroid hormone, calcium, and phosphorus levels. A non-contrast computed tomography of the head was done in 2013 and it showed finely speckled subcutaneous calcifications in the high convexity of the head. Cutaneous exploration did not show any abnormality. We herein report an unusual case of late-onset scalp calcifications in a patient with PPHP.

[Renal biopsies during the second trimester of pregnancy: report of two cases]. / Biopsia renal en el segundo trimestre del embarazo: Dos casos clínicos.

Kidney biopsies were performed in two women during their 21st and 24th week of pregnancy. The first patient developed an abrupt nephrotic syndrome without hypertension or kidney failure. The pathological study disclosed diffuse podocyte alterations such as those observed in focal and segmental glomerulosclerosis, which had a good response to steroidal treatment. The second patient had a progressive renal failure associated with non-nephrotic proteinuria. The biopsy disclosed a fibrillary glomerulopathy.

Primary Rectal Tumor With Extensive Choriocarcinoma Differentiation in a Woman With Lung, Liver and Disseminated Peritoneal Disease: A Primary Rectal Adenocarcinoma With Extensive Choriocarcinoma Differentiation or Primary Rectal Choriocarcinoma?

Primary rectal adenocarcinoma with extensive choriocarcinomatous differentiation is a rare neoplasm, with only sporadic cases reported worldwide. The prognosis is typically poor, and no standard therapy has been established for this tumor. We report a case of a 63-year-old woman who presented with lower abdominal and pelvic discomfort, as well as rectal bleeding. Endoscopy revealed a rectal tumor. She was diagnosed with primary rectal adenocarcinoma with extensive choriocarcinomatous differentiation, accompanied by liver metastasis and peritoneal carcinomatosis. The immunohistochemical profile demonstrated strong and diffuse positivity for keratin (AE1/AE3), beta-human chorionic gonadotropin (ß-HCG), p53, MYC, p16, and Ki-67. Molecular analysis indicated mutations in KRAS, TP53, and PI3KCA. Despite the tumor's profile, the serum ß-HCG level was not elevated. A chemotherapy regimen for metastatic colorectal adenocarcinoma was initiated, but there was a poor response, with rapid tumor progression. The patient survived for only 5 months postdiagnosis. We discuss the histopathological, immunohistochemical, and molecular findings, emphasizing their relevance to the differential diagnosis of neoplasms with choriocarcinomatous differentiation.

Continuous Subcutaneous Insulin Infusion in Type 1 Diabetes Mellitus Patients: Results from the Spanish National Registry.

Aim: To analyze the clinical effect of continuous subcutaneous insulin infusion (CSII) in type 1 diabetes mellitus (T1D) patients in the Spanish real-world scenario. Methods: All T1D patients on CSII registered in the SPAnish Insulin Pump (SPAIP) registry were included. The primary efficacy outcome was change in HbA1c during follow-up. Secondary efficacy outcomes included: insulin pump indications, diabetes complication rates, insulin and pump use, and continuous glucose monitoring (CGM) glycometrics. Patient data were typed through the web-based SPAIP registry. Results: Data from 2979 T1D patients treated with CSII were analyzed. The median age was 44 years (interquartile range [IQR] 34-52 years), and T1D duration was 27 years (IQR 18-35 years). The median duration of CSII therapy was 6 years (IQR 3-10 years). The main indications for treatment were suboptimal glycemic control (33.8%), hypoglycemia (22.1%), and increased glycemic variability (18.8%). Glycated hemoglobin decreased by 6 mmol/mol (95% CI, -5 to -6 mmol/mol, P < 0.001) [-0.5%, 95% CI, -0.4 to -0.5, P < 0.001] during the follow-up. The percentage of patients with severe hypoglycemia decreased from 14.9% to 0.9% (P < 0.001). We observed an inverse correlation between final HbA1c levels and CGM adherence (R = -0.24, P < 0.001) or percentage of time with active hybrid closed-loop functions (R = -0.25, P < 0.001). Conclusions: CSII treatment was associated with a sustained improvement in glycemic control in the Spanish population. This benefit was greater among patients with higher CGM or active hybrid closed-loop functions adherence. The protocol was publicly registered at ClinicalTrials.gov (NCT04761094).

"Single nucleotide polymorphisms of the OPG/RANKL system genes in primary hyperparathyroidism and their relationship with bone mineral density".

BACKGROUND: Primary hyperparathyroidism (PHPT) affects mainly cortical bone. It is thought that parathyroid hormone (PTH) indirectly regulates the activity of osteoclasts by means of the osteoprotegerin/ligand of the receptor activator of nuclear factor-κß (OPG/RANKL) system. Several studies have confirmed that OPG (osteoprotegerin) and RANKL (ligand of the receptor activator of nuclear factor-κß) loci are determinants of bone mineral density (BMD) in the general population. The aim of this study is to analyze the relationship between fractures and BMD and the rs3102735 (163 A/G), rs3134070 (245 T/G) and rs2073618 (1181 G/C) SNPs of the OPG and the rs2277438 SNP of the RANKL, in patients with sporadic PHPT. METHODS: We enrolled 298 Caucasian patients with PHPT and 328 healthy volunteers in a cross-sectional study. We analyzed anthropometric data, history of fractures or renal lithiasis, biochemical determinants including markers for bone remodelling, BMD measurements in the lumbar spine, total hip, femoral neck and distal radius, and genotyping for the SNPs to be studied. RESULTS: Regarding the age of diagnosis, BMI, menopause status, frequency of fractures or renal lithiasis, we found no differences between genotypes in any of the SNPs studied in the PHPT group. Significant lower BMD in the distal radius with similar PTH levels was found in the minor allele homozygotes (GG) compared to heterozygotes and major allele homozygotes in both OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs in those with PHPT compared to control subjects. We found no differences between genotypes of the OPG rs2073618 (1181 G/C) SNP with regard to BMD in the PHPT subjects. In the evaluation of rs2277438 SNP of the RANKL in PHPT patients, we found a non significant trend towards lower BMD in the 1/3 distal radius and at total hip in the minor allele homocygotes (GG) genotype group versus heterocygotes and major allele homocygotes (AA). CONCLUSIONS: Our study provides the first evaluation of the relationship between SNPs of the OPG/RANK system and sporadic PHPT. Subjects with PHPT and minor homocygote genotype (GG) for the OPG rs3102735 (163 A/G) and OPG rs3134070 (245 T/G) SNPs have lower BMD in the distal radius, and this association does not appear to be mediated by differences in PTH serum levels.

Bone mineral density evolution and incidence of fractures in a cohort of patients with primary hyperparathyroidism treated with parathyroid surgery vs active surveillance during 6 years of follow-up. / Evolución de la densidad mineral ósea y aparición de fracturas en una cohorte de pacientes con hiperparatiroidismo primario tratados con cirugía paratiroidea vs. vigilancia activa sin cirugía en 6 años de seguimiento.

INTRODUCTION: The need for parathyroidectomy to treat asymptomatic patients with primary hyperparathyroidism is controversial. The aim of this study was to assess the impact of parathyroidectomy vs. surveillance on skeletal outcomes such as bone mineral density (BMD) and incident fractures. METHODS: This was a retrospective cohort study including 170 patients (112 treated with surgery and 58 subject to active surveillance) between 1991 and 2014. Changes in BMD in lumbar spine, femoral neck, total hip, and radius, and incidence of fractures, were monitored for 2-6 years. RESULTS: Patients treated with surgery had BMD gains at 2years of 4.37%, as compared to 1.59% in non-operated patients (p<0.05) in the lumbar spine, 3.90% vs. 0.19% (p<0.05) in the femoral neck, and 2.70% vs. 0.14% (p<0.05) in total hip. Gain in BMD in the lumbar spine and femoral neck remained significant in operated patients at 4 and 6 years. No improvement was seen in the radius in operated patients. No significant difference was seen in fracture occurrence between operated and non-operated patients. CONCLUSION: Patients with primary hyperparathyroidism treated with surgery experience greater BMD gains than non-operated patients, especially in the lumbar spine and femoral neck. The risk of fracture does not decrease in the group of operated patients.

Analysis of the influence of the T393C polymorphism of the GNAS gene on the clinical expression of primary hyperparathyroidism.

BACKGROUND: The receptor of parathyroid hormone and parathyroid hormone-related-protein (PTH/PTHrp) is located in the cell membrane of target tissues - kidney and osteoblasts. It is a G protein-coupled-receptor whose Gsα subunit is encoded by the GNAS gene. Our aim was to study whether the single nucleotide polymorphism (SNP) T393C of the GNAS gene is associated with renal stones, bone mineral density (BMD), or bone remodelling markers in primary hyperparathyroidism (PHPT). METHODS: An analysis was made of clinical and biochemical parameters and densitometric values in three areas and their relationship with the T393C SNP of the GNAS gene in 261 patients with primary hyperparathyroidism and in 328 healthy controls. Genotyping was performed using the Custom Taqman® SNP Genotyping assay. RESULTS: The genotype frequencies of GNAS T/C 393 were similar in the control and PHPT groups. No association was found between genotypes and clinical expression of PHPT (renal stones and bone fractures). A nonstatistically significant trend was seen to lower BMD in the lumbar spine, femoral neck, and total hip in both PHPT and control C homozygote subjects. CONCLUSION: Genetic susceptibility to PHPT related to the GNAS T393C polymorphism or a major influence in its development and clinical expression were found. A C allele-related susceptibility to lower BMD in trabecular bone in both PHPT and control subjects is not sufficient to suggest a more severe clinical expression of PHPT. This trend may be considered as a basis for further studies with larger sample sizes and complementary functional evaluation.

Reductive coupling of terpenic allylic halides catalyzed by Cp2TiCl: a short and efficient asymmetric synthesis of onocerane triterpenes.

[reaction: see text] Titanocene chloride catalyzes the regioselective alpha,alpha'-homocoupling of terpenic allylic halides. This process has been employed in the short and effective synthesis of terpenoids such as beta-onoceradiene (1), beta-onocerin (2), and squalene (3). Evidence is presented for eta1-allyltitanium species being involved in the coupling.

Percepción De Los Padres De Niños Con Déficit Ejecutivos Que Presentan Dificultades En El Aprendizaje De Matemáticas / Parental Perception In Children With Executive Deficits Who Have Learning Difficulties In Mathemathics

RESUMEN El objetivo principal de esta investigación es describir los déficits ejecutivos de los niños/as que presentan dificultades de aprendizaje en el área de matemáticas y su relación con las percepciones paternas. Se estudió una muestra de 30 niños con dificultades en el área de matemáticas en edades comprendidas entre los 9 y 12 años, a los cuales se les aplicó la Torre de Londres, y a los padres, el Inventario Infantil de Funciones Ejecutivas (CHEXI). De acuerdo a las pruebas aplicadas, los resultados mostraron déficit en memoria de trabajo, planificación, regulación e inhibición. Los resultados muestran que no existe correlación entre los déficits ejecutivos evidenciados en los niños y la percepción de los padres. Sin embargo, existe relación positiva entre la percepción de los padres en el área de memoria de trabajo y el bajo rendimiento académico. Los resultados se discuten por la complejidad del constructo evaluado y las múltiples variables que intervienen al momento de su valoración clínica.

ABSTRACT The main objective of this research is to describe the executive deficits of children with learning difficulties in mathematics and their relationship with parental perceptions. A sample of 30 children with difficulties in mathematics at ages between 9 and 12 years was studied, they underwent Tower of London test, and to the parents the Children's Inventory of Executive Functions (CHEXI) was studied. According to the applied tests, the results showed difficulties in working memory, planning, regulation and inhibition. The results showed no correlation between the executive deficits evidenced in children and the perception of parents. However, there is a positive relationship between the perception of parents in the area of working memory and poor academic performance. The results are discussed by the complexity of the evaluated construct and the multiple variables involved at the time of its clinical assessment.

Alta frecuencia de dislipidemias en niños y adolescentes con Síndrome de Down / High frequency of dyslipidemia in children and adolescents with Down Syndrome

El síndrome de Down (SD) presenta mayor riesgo de desarrollar enfermedades crónicas asociadas a mayor morbimortalidad por enfermedad cardiovascular. Algunos estudios han mostrado un peor perfil lipídico en niños con SD, sin embargo, hasta el momento no existen recomendaciones de tamizaje para dislipidemia en estos pacientes. Objetivo: Describir la frecuencia de dislipidemia en una población chilena de niños y adolescentes con SD. Pacientes y Método: Estudio retrospectivo, que incluyó pacientes con SD entre 2 y 18 años, participantes de un programa de salud para personas con SD en la Red de Salud UC CHRISTUS, entre los años 2007 y 2015. Se incluyeron pacientes que tuvieran perfil lipídico tomado entre sus exámenes de rutina. Se registraron características clínicas, comorbilidades relevantes, malformaciones, medicamentos, estado nutricional y estado puberal. El diagnóstico de dislipidemias se realizó de acuerdo a los criterios de la NHLBI 2011. Resultados: Se revisaron las fichas clínicas de 218 niños con SD, 58,3% tenía algún tipo de dislipidemia. Las más frecuentes fueron colesterol HDL bajo (15,1%) e hipertrigliceridemia (12,8%). La dislipidemia aterogénica (C-HDL bajo más hipertrigliceridemia) fue la dislipidemia combinada más frecuente (13,3%), la cual no se asoció a sobrepeso u obesidad. Conclusiones: Se encontró una alta frecuencia de dislipidemia en niños y adolescentes chilenos con SD. Nuestros resultados nos hacen sugerir la realización de un perfil lipídico de forma temprana a todos los pacientes con SD, independiente de la presencia de factores de riesgo de dislipidemia.

Down Syndrome (DS) shows an increased risk of chronic diseases, associated to higher morbidity and mortality for cardiovascular disease. Some studies have shown a worse lipid profile in children with DS, however, until now there is no recommendation for screening for dyslipidemia in these subjects. Objective: To describe the frequency of dyslipidemia in a population of Chilean children and adolescents with DS. Patients and Method: Retrospective study, including patients with DS, aged 2 to 18 years, who participated in a special health care program for people with DS in Health Net UC CHRISTUS, between 2007 and 2015. Patients who had a lipid profile between their routine laboratory tests were included. Clinical characteristics, relevant comorbidities, malformations, medications, nutritional status and pubertal development were obtained from medical records. Diagnosis of dyslipidemia was considered according to the criteria of the NHLBI 2011. Results: The medical records of 218 children with DS were revised, 58,3% had some type of dyslipidemia. The most frequent single dyslipidemias were low HDL Chol (15,1%) and hypertriglyceridemia (12,8%). Atherogenic dyslipidemia (low HDL plus hypertriglyceridemia) was the most frequent combined dyslipidemia (13,3%). The occurrence of atherogenic dyslipidemia was not associated with overnutrition and obesity. Conclusions: A high frequency of dyslipidemia was found in Chilean children and adolescents with DS. Our results make us suggest that lipid profile should be performed early in all patients with DS, independent of the presence of risk factors for dyslipidemia.