Genetic profile of a large Spanish cohort with hypercalcemia.

Introduction: The disorders in the metabolism of calcium can present with manifestations that strongly suggest their diagnosis; however, most of the time, the symptoms with which they are expressed are nonspecific or present only as a laboratory finding, usually hypercalcemia. Because many of these disorders have a genetic etiology, in the present study, we sequenced a selection of 55 genes encoding the principal proteins involved in the regulation of calcium metabolism. Methods: A cohort of 79 patients with hypercalcemia were analyzed by next-generation sequencing. Results: The 30% of our cohort presented one pathogenic or likely pathogenic variant in genes associated with hypercalcemia. We confirmed the clinical diagnosis of 17 patients with hypocalciuric hypercalcemia (pathogenic or likely pathogenic variants in the CASR and AP2S1 genes), one patient with neonatal hyperparathyroidism (homozygous pathogenic variant in the CASR gene), and another patient with infantile hypercalcemia (two pathogenic variants in compound heterozygous state in the CYP24A1 gene). However, we also found variants in genes associated with primary hyperparathyroidism (GCM2), renal hypophosphatemia with or without rickets (SLC34A1, SLC34A3, SLC9A3R1, VDR, and CYP27B1), DiGeorge syndrome (TBX1 and NEBL), and hypophosphatasia (ALPL). Our genetic study revealed 11 novel variants. Conclusions: Our study demonstrates the importance of genetic analysis through massive sequencing to obtain a clinical diagnosis of certainty. The identification of patients with a genetic cause is important for the appropriate treatment and identification of family members at risk of the disease.

Primary Cutaneous CD4 Small/Medium T-Cell Lymphoproliferative Disorder Following COVID-19 Vaccination-What Do We Know about Lymphoproliferative Disorders and Cutaneous Lymphomas after COVID-19 Vaccination? A Report of an Atypical Case and a Review of the Literature.

The association between Primary cutaneous CD4 small/medium T-cell lymphoproliferative disorder (PCSM-TCLPD) and COVID-19 immunization has been sparsely documented in the medical literature. Reviewing the literature, albeit infrequently, we can find cases of the recurrence and new onset of lymphoproliferative processes and cutaneous lymphomas following the COVID-19 vaccine. Many of the entities we encounter are classified as cutaneous lymphoproliferative disorders. The prevailing hypothesis suggests that the predominant cutaneous reactions to SARS-CoV-2 vaccines may stem from T-cell-mediated immune activation responses to vaccine components, notably messenger RNA (mRNA). Specifically, it is posited that the presence of cutaneous lymphoid infiltrates may be linked to immune system stimulation, supported by the absence, to date, of instances of primary cutaneous B-cell lymphoma following mRNA vaccination. Within this context, it is imperative to underscore that the etiological association between PCSM-TCLPD and COVID-19 vaccination should not discourage vaccination efforts. Instead, it underscores the necessity for continuous surveillance, in-depth investigation, and comprehensive follow-up studies to delineate the specific attributes and underlying mechanisms of such cutaneous manifestations post vaccination.

IMP3 Immunohistochemical Expression Is Related with Progression and Metastases in Xenografted and Cutaneous Melanomas.

INTRODUCTION: Insulin-like growth factor-II messenger RNA-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective was to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. We test the effect of radiotherapy (RT) and mesenchymal stromal cells (MSCs) treatment, analyzing the tumorigenic and metastatsizing capacity in a mice melanoma xenograft model. MATERIALS AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice (n = 64). We established a control group, a group treated with MSCs, a group treated with MSCs plus RT, and a group treated with RT. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous superficial spreading melanoma (n = 104) and nodular melanoma (n = 10) with at least 5 years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the 2 cell lines. The A375 cell line induced the formation of metastases, while the G361 cell line provoked tumor formation but not metastases. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (p = 0.000, one-way ANOVA test) and reduced the number of metastases (p = 0.004, one-way ANOVA test). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT + MSCs in the A357 tumor cell line, and 89.84% RT + MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation (measured by the expression of Ki-67), the number of metastases, and reduced expression of adhesion molecules. CONCLUSIONS: The combined treatment of RT and MSCs on xenografted melanomas reduces tumor size, metastases frequency, and the epithelial to mesenchymal transition/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin), and molecules related with prognosis (IMP3).

Diversity patterns of vascular and non-vascular epiphytes along tropical dry forest / Patrones de diversidad de epífitas vasculares y no vasculares a lo largo del bosque seco tropical

Abstract Introduction: Epiphytes (vascular and non-vascular) are one of the most diverse groups in the Neotropics, but despite their importance in the functioning of many ecosystems, much of their taxonomy and ecology is still unknown in the dry forest of Colombia. Objective: To compare the diversity patterns and species composition of vascular and non-vascular epiphytes along tropical dry forest remnants of Cauca Valley, Colombia. Methods: Ten permanent plots (50 x 20 m2) were established in tropical dry forest remnants. The epiphytes were sampled in 40-50 trees per plot. Alpha and gamma diversity were calculated using the richness (q0) and Shannon index (q1) (alpha was estimated as the average for phorophytes). Beta diversity was measured using the Whitaker index. To evaluate the relationship between diversities and environmental variables, GLM analysis was used. Results: We found 50 morphospecies of vascular epiphytes, 77 of bryophytes and 290 of lichens. The 𝛼 and 𝛾 diversity of bryophytes from each remnant was significantly explained by temperature. The abundance of lichens per tree was significantly related with the DBH and tree height of each remnant. The 𝛼 diversity of vascular epiphytes shown can be explained by temperature and precipitation. The 𝛾 diversity was strongly influenced by the beta diversity in bryophytes and lichens. This pattern is because the sites with high disturbance present a lower diversity, as a consequence of a homogenizing effect, that is, a low turnover of species between sampling units. Conclusions: Precipitation and temperature affected the diversity of bryophytes and vascular epiphytes, while it did not show a relationship with the lichen's diversity, for which there is not a high congruence between the diversity and composition of these epiphytes.

Resumen Introducción: Los epífitos (vasculares y no vasculares) son uno de los más diversos grupos de plantas en el Neotrópico, pero a pesar de su importancia para el funcionamiento de varios ecosistemas, existen grandes vacíos en su conocimiento taxonómico y ecológico en el bosque seco de Colombia. Objetivo: Comparar los patrones de diversidad y composición de especies de epífitas vasculares y no vasculares a lo largo de remanentes de bosque seco tropical del Valle del Cauca, Colombia. Métodos: Se establecieron diez parcelas permanentes (50 x 20 m2) en remanentes de bosque seco tropical. Las epífitas se muestrearon en 40-50 árboles por parcela. La diversidad alfa y gamma se calculó utilizando la riqueza (q0) y el índice de Shannon (q1) (alfa se estimó como el promedio para los forófitos). La diversidad beta se midió utilizando el índice de Whitaker. Para evaluar la relación entre diversidades y variables ambientales se utilizó el análisis GLM. Resultados: Se encontraron 50 morfoespecies de epífitas vasculares, 77 de briófitas y 290 de líquenes. La diversidad de 𝛼 y 𝛾 de briófitas de cada remanente fue explicada significativamente por la temperatura. La abundancia de líquenes por árbol se relacionó significativamente con el DAP y la altura del árbol de cada remanente. La diversidad 𝛼 de epífitas vasculares que se muestra puede explicarse por la temperatura y la precipitación. La diversidad 𝛾 estuvo fuertemente influenciada por la diversidad beta en briófitas y líquenes. Este patrón se debe a que los sitios con alta perturbación presentan una menor diversidad, como consecuencia de un efecto homogeneizador, es decir, un bajo recambio de especies entre unidades de muestreo. Conclusiones: La precipitación y la temperatura afectaron la diversidad de briófitas y epífitas vasculares, mientras que no mostró relación con la diversidad de líquenes, por lo que no existe una alta congruencia entre la diversidad y composición de estas epífitas.

Genotypic variability in patients with clinical diagnosis of Bartter syndrome type 3.

Bartter syndrome (BS) is a salt-losing hereditary tubulopathy characterized by hypokalemic metabolic alkalosis with secondary hyperaldosteronism. Confirmatory molecular diagnosis may be difficult due to genetic heterogeneity and overlapping of clinical symptoms. The aim of our study was to describe the different molecular findings in patients with a clinical diagnosis of classic BS. We included 27 patients (26 families) with no identified pathogenic variants in CLCNKB. We used a customized Ion AmpliSeq Next-Generation Sequencing panel including 44 genes related to renal tubulopathies. We detected pathogenic or likely pathogenic variants in 12 patients (44%), reaching a conclusive genetic diagnosis. Variants in SLC12A3 were found in 6 (Gitelman syndrome). Median age at diagnosis was 14.6 years (range 0.1-31), with no history of prematurity or polyhydramnios. Serum magnesium level was low in 2 patients (33%) but urinary calcium excretion was normal or low in all, with no nephrocalcinosis. Variants in SLC12A1 were found in 3 (BS type 1); and in KCNJ1 in 1 (BS type 2). These patients had a history of polyhydramnios in 3 (75%), and the mean gestational age was 34.2 weeks (SD 1.7). The median age at diagnosis was 1.8 years (range 0.1-6). Chronic kidney disease and nephrocalcinosis were present in 1 (25%) and 3 (75%) patients, respectively. A variant in CLCN5 was found in one patient (Dent disease), and in NR3C2 in another patient (Geller syndrome). Genetic diagnosis of BS is heterogeneous as different tubulopathies can present with a similar clinical picture. The use of gene panels in these diseases becomes more efficient than the study gene by gene with Sanger sequencing.

Localized Cutaneous Nodular Amyloidosis in a Patient with Sjögren's Syndrome.

Primary localized cutaneous nodular amyloidosis (PLCNA) is included in the primary forms of cutaneous amyloidosis along with macular and lichenoid amyloidosis. It is a rare disease attributed to plasma cell proliferation and deposition of immunoglobulin light chains in the skin. We present the case of a 75-year-old woman with a personal history of Sjogren's syndrome (SjS), who consulted for asymptomatic yellowish, waxy nodules on the left leg. Dermoscopy of the lesions showed a smooth, structureless, yellowish surface with hemorrhagic areas and few telangiectatic vessels. Histopathology revealed an atrophic epidermis and deposits of amorphous eosinophilic material in the dermis with a positive Congo red stain. The diagnosis of nodular amyloidosis was made. Periodic reevaluation was indicated after the exclusion of systemic amyloidosis. PLCNA is often associated with autoimmune connective tissue diseases, and up to 25% of all PLCNA cases occur in patients with SjS. Therefore, in addition to ruling out systemic amyloidosis, screening for possible underlying SjS should be performed when the diagnosis of PLCNA is confirmed.

Localized Cutaneous Nodular Amyloidosis: A Specific Cutaneous Manifestation of Sjögren's Syndrome.

Primary localized cutaneous nodular amyloidosis (PLCNA) is a rare condition attributed to plasma cell proliferation and the deposition of immunoglobulin light chains in the skin without association with systemic amyloidosis or hematological dyscrasias. It is not uncommon for patients diagnosed with PLCNA to also suffer from other auto-immune connective tissue diseases, with Sjögren's syndrome (SjS) showing the strongest association. This article provides a literature review and descriptive analysis to better understand the unique relationship between these two entities. To date, 34 patients with PLCNA and SjS have been reported in a total of 26 articles. The co-existence of PLCNA and SjS has been reported, especially in female patients in their seventh decade of life with nodular lesions on the trunk and/or lower extremities. Acral and facial localization, which is a typical localization of PLCNA in the absence of SjS, seems to be much more unusual in patients with associated SjS.

25(OH)Vitamin D Deficiency and Calcifediol Treatment in Pediatrics.

Vitamin D is essential for the normal mineralization of bones during childhood. Although diet and adequate sun exposure should provide enough of this nutrient, there is a high prevalence of vitamin D deficiency rickets worldwide. Children with certain conditions that lead to decreased vitamin D production and/or absorption are at the greatest risk of nutritional rickets. In addition, several rare genetic alterations are also associated with severe forms of vitamin-D-resistant or -dependent rickets. Although vitamin D3 is the threshold nutrient for the vitamin D endocrine system (VDES), direct measurement of circulating vitamin D3 itself is not a good marker of the nutritional status of the system. Calcifediol (or 25(OH)D) serum levels are used to assess VDES status. While there is no clear consensus among the different scientific associations on calcifediol status, many clinical trials have demonstrated the benefit of ensuring normal 25(OH)D serum levels and calcium intake for the prevention or treatment of nutritional rickets in childhood. Therefore, during the first year of life, infants should receive vitamin D treatment with at least 400 IU/day. In addition, a diet should ensure a normal calcium intake. Healthy lifestyle habits to prevent vitamin D deficiency should be encouraged during childhood. In children who develop clinical signs of rickets, adequate treatment with vitamin D and calcium should be guaranteed. Children with additional risk factors for 25(OH)D deficiency and nutritional rickets should be assessed periodically and treated promptly to prevent further bone damage.

Características clínico-patológicas de pacientes jóvenes con cáncer de mama en un centro oncológico en Medellín / Clinical and pathological characteristics of young patients with breast cancer at a cancer center in Medellin

Introducción: El cáncer de mama es la principal neoplasia en mujeres y se ha reportado un aumento de la incidencia en jóvenes menores a 40 años. El objetivo del presente estudio fue describir las características clínicas y patológicas, de pacientes con cáncer de mama invasor, ≤40 años, atendidas en un centro de referencia oncológico en Medellín-Colombia. Metodología: Se realizó un estudio transversal, realizado en la Clínica Vida (Fundación Colombiana de Cancerología), en el período enero del 2015 a diciembre del 2019. La muestra fue no probabilística, de pacientes con diagnóstico oncológico de cáncer de mama invasor. Se registró edad, tipo de cáncer, antecedentes familiares, recidivas y mortalidad. Se utiliza estadística descriptiva. Resultados: De 2332 casos de nuevos de cáncer de mama invasor, 261 se identificaron en mujeres ≤ 40 años, 11.19 % (IC 95 % 11.17-11.22 %), edad de 34.2 ± 4 años. 16.5 % en menores de 30 años, 40.2 % en edad de 30 a 45 años y 42.2 % en mujeres de 35 a 40 años. La presentación principal fue masa palpable auto detectada. El subtipo molecular Luminal A 16 %, Luminal B 48.3 %, Her2 enriquecido 11.2 % y Triple negativo 21.6 %. El 27 % tuvo algún antecedente familiar. La recidiva fue del 14 % y la mortalidad del 14.9 %. Conclusión: El 11 % de pacientes con cáncer de mama en esta serie corresponde a mujeres jóvenes, con una presentación en estadios más avanzados y biología molecular desfavorable, lo cual requirió un manejo más agresivo y radical. Esto resalta la importancia del diagnóstico oportuno en pacientes de lesiones mamarias en mujeres jóvenes.

Introduction: Breast cancer is the main neoplasm in women, and an increased incidence has been reported in young people under 40 years of age. The objective of the present study was to describe the clinical and pathological characteristics of patients with invasive breast cancer, ≤40 years old, treated at a reference oncology center in Medellín-Colombia. Methodology: A cross-sectional study was carried out by the Vida Clinic (Colombian Cancer Foun-dation) from January 2015 to December 2019. The sample was nonprobabilistic of patients with an oncological diagnosis of invasive breast cancer. Age, type of cancer, family history, recurrence, and mortality were recorded. Descriptive statistics are used. Results: Of 2332 cases of new invasive breast cancer, 261 were identified in women ≤ 40 years, 11.19% (95% CI 11.17-11.22%), age 34.2±4 years. 16.5% in those under 30 years of age, 40.2% in women between 30 and 45 years of age, and 42.2% in women between 35 and 40 years of age. The main presentation was a self-detected palpable mass. The molecular subtypes luminal A 16%, luminal B 48.3%, Her2 enriched 11.2%, and triple-negative 21.6%. A total of 27% had a family history. Recurrence was 14%, and mortality was 14.9%. Conclusion: Eleven percent of patients with breast cancer in this series were young women, with a presentation in more advanced stages and unfavorable molecular biology, which requires more aggressive and radical management. This highlights the importance of timely diagnosis in young women with breast injuries.

Tissue Engineering and Regeneration of the Human Hair Follicle in Androgenetic Alopecia: Literature Review.

Androgenetic alopecia (AGA) is an androgen-dependent process and represents the most frequent non-scarring alopecia. Treatments for AGA do not always achieve a satisfactory result for the patient, and sometimes cause side effects that lead to discontinuation of treatment. AGA therapeutics currently includes topical and oral drugs, as well as follicular unit micro-transplantation techniques. Tissue engineering (TE) is postulated as one of the possible future solutions to the problem and aims to develop fully functional hair follicles that maintain their cyclic rhythm in a physiological manner. However, despite its great potential, reconstitution of fully functional hair follicles is still a challenge to overcome and the knowledge gained of the key processes in hair follicle morphogenesis and biology has not yet been translated into effective replacement therapies in clinical practice. To achieve this, it is necessary to research and develop new approaches, techniques and biomaterials. In this review, present and emerging hair follicle bioengineering strategies are evaluated. The current problems of these bioengineering techniques are discussed, as well as the advantages and disadvantages, and the future prospects for the field of TE and successful hair follicle regeneration.

Pulmonary Artery Perforation by Atrial Appendage Closure Device and the Contribution of Auricular Contraction to Its Pathogenesis.

We report the case of an 83-year-old man with paroxysmal atrial fibrillation who underwent successful percutaneous left atrial appendage closure with the LAmbre device, being in sinus rhythm at implantation. Suddenly, the patient experienced cardiac tamponade and died within a few minutes. Autopsy revealed a slight protrusion of the LAmbre device into the atrial appendage wall, and pulmonary artery laceration. This is the first published report of pulmonary artery perforation by the LAmbre device. This case highlights the need for a detailed imaging study before this procedure is performed, to assess left atrial appendage movement/contraction in patients in sinus rhythm.

Nous présentons le cas d'un homme de 83 ans atteint de fibrillation auriculaire paroxystique qui était en rythme sinusal lors de l'implantation réussie du dispositif de fermeture de l'appendice auriculaire LAmbre par voie percutanée. Le patient a soudainement subi une tamponnade cardiaque et est mort en quelques minutes. L'autopsie a révélé que le dispositif LAmbre formait une légère saillie dans la paroi de l'appendice auriculaire et qu'il avait occasionné une lacération de l'artère pulmonaire.C'est la première fois qu'un cas de perforation de l'artère pulmonaire par le dispositif LAmbre est publié. Ce cas montre l'importance de faire un examen d'imagerie complet pour évaluer le mouvement et la contraction de l'appendice auriculaire gauche chez les patients en rythme sinusal avant de réaliser l'intervention.

Depresión mayor en población general de Envigado (Colombia): prevalencia y factores asociados / Major depression in the general population of Envigado (Colombia): prevalence and associated factors

Resumen Introducción: La depresión afecta a más de 300 millones de personas en el mundo, es la principal causa de discapacidad y contribuye de forma importante a la carga mundial de morbilidad. Objetivo: Determinar la prevalencia y algunos factores personales, sociales y familiares asociados al trastorno de depresión mayor en población de 15 a 65 años del municipio de Envigado (Colombia) en el año 2017. Método: Estudio transversal con intención analítica, a partir de la información de 905 participantes del "Estudio Poblacional de Salud Mental, Envigado 2017", recopilada a través de entrevistas realizadas con la World Health Organization Composite International Diagnostic Interview -CIDI-OMS. El procesamiento se realizó mediante el programa SPSS versión 23. Resultados: Cuatro factores explican la probabilidad de depresión mayor en el último año, en la población de estudio: el abuso de drogas diferentes al alcohol (ORaj=4,43 [1,164-16,833]), la muerte o enfermedad de un familiar cercano (ORaj=4,15 [1,583-10,880]), presentar altos niveles de resiliencia (ORaj=0,22 [0,112-0,425]) y una percepción excelente o buena de su salud mental (ORaj=0,19 [0,098-0,378]). Conclusiones: Los factores que aumentan la probabilidad de depresión mayor en la población de estudio son: abuso de drogas diferentes al alcohol y la muerte o enfermedad de un familiar de primer grado de consanguinidad; y los factores protectores son altos niveles de resiliencia y una percepción excelente o buena de la propia salud mental. Esta evidencia refuerza la necesidad de implementar programas de promoción centrados en el mejoramiento de habilidades para la vida, que propicien estrategias adecuadas frente a los desafíos.

Abstract Introduction: Depression affects more than 300 million people in the world, it is the leading cause of disability and contributes significantly to the global burden of disease. Objective: To determine the prevalence and some social, personal, and family factors associated with major depressive disorder in a population aged from 15 to 65 in Envigado (Colombia) in 2017. Methods: A cross-sectional study with analytical intent was conducted, based on the information from 905 participants for the "Population study of mental health 2017", collected through interviews administered by means of the World Health Organization Composite International Diagnostic Interview -CIDI-OMS. The processing was performed using the SPSS program version 23. (CES University License). Results: Four factors correlate with major depression in the last year in the study population: drug abuse other than alcohol (ORaj = 4,43 [1,164-16,833]), a close relative´s death or illness (ORaj = 4,15 [1,583-10,880]), high resilience (ORaj = 0.22 [0,112-0,425]) and an excellent or good mental health perception (ORaj = 0.19 [0.098-0.378]). Conclusions: the factors that increase the probability of major depression in the study population are drug abuse other than alcohol and the death or illness of a first-degree relative; and the protective factors are high levels of resilience and an excellent or good perception of one's own mental health. This evidence reinforces the need to implement promotion programs focused on improvement of life skills, which provide adequate strategies to face the challenges.

Acidosis tubular renal distal hereditaria: correlación genotípica, evolución a largo plazo y nuevas perspectivas terapéuticas / Hereditary distal renal tubular acidosis: Genotypic correlation, evolution to long term, and new therapeutic perspectives

La acidosis tubular renal distal (ATRD) es una enfermedad rara que se debe al fallo del proceso normal de acidificación de la orina a nivel tubular distal y colector. Se caracteriza por una acidosis metabólica hiperclorémica persistente, con anión gap normal en plasma, en presencia de un pH urinario elevado y baja excreción urinaria de amonio. Se han descrito hasta el momento 5 genes cuyas mutaciones dan lugar a ATRD primaria. Las alteraciones de los genes ATP6V1B1 y ATP6V0A4 se heredan de forma recesiva y están asociadas a formas de inicio más precoces y con sordera neurosensorial en muchos casos. Las variantes patogénicas en el gen SLC4A1 se heredan habitualmente de forma dominante y dan lugar a cuadros más leves, con un diagnóstico más tardío y alteraciones electrolíticas menores. Sin embargo, la evolución a nefrocalcinosis y litiasis, y el desarrollo de enfermedad renal crónica a medio-largo plazo se ha descrito de forma similar en estos 3grupos. Por último, se han descrito también formas recesivas de ATRD asociadas a mutaciones en los genes FOXI1 y WDR72. El manejo clínico de la ATRD se basa en sales de bicarbonato o citrato, que no logran corregir en todos los casos las alteraciones metabólicas descritas y, por lo tanto, las consecuencias asociadas a ellas. Recientemente, un nuevo tratamiento basado en sales de bicarbonato y citrato de liberación prolongada ha recibido la denominación de medicamento huérfano en Europa para el tratamiento de la ATRD. (AU)

Distal renal tubular acidosis (DRTA) is a rare disease resulting from a failure in the normal urine acidification process at the distal tubule and collecting duct level. It is characterised by persistent hyperchloremic metabolic acidosis, with a normal anion gap in plasma, in the presence of high urinary pH and low urinary excretion of ammonium. To date, 5 genes whose mutations give rise to primary DRTA have been described. Alterations in the ATP6V1B1 and ATP6V0A4 genes are inherited recessively and are associated with forms of early onset and, in many cases, with neurosensorial deafness. Pathogenic variants in the SLC4A1 gene are habitually inherited dominantly and give rise to milder symptoms, with a later diagnosis and milder electrolytic alterations. Nonetheless, evolution to nephrocalcinosis and lithiasis, and the development of chronic kidney disease in the medium to long term has been described in a similar manner in all 3groups. Lastly, recessive forms of DTRA associated to mutations in the FOXI1 and WDR72 genes have also been described. The clinical management of DTRA is based on bicarbonate or citrate salts, which do not succeed in correcting all cases of the metabolic alterations described and, thus, the consequences associated with them. Recently, a new treatment based on slow-release bicarbonate and citrate salts has received the designation of orphan drug in Europe for the treatment of DTRA. (AU)

Molecular aspects and long-term outcome of patients with primary distal renal tubular acidosis.

BACKGROUND: Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder caused by impaired distal mechanisms of urinary acidification. Most cases are secondary to pathogenic variants in ATP6V0A4, ATP6V1B1, and SLC4A1 genes, which encode transporters regulating acid-base balance in the collecting duct. METHODS: Retrospective study of molecular and clinical data from diagnosis and long-term follow-up (10, 20, and 40±10 years) of 16 patients with primary dRTA diagnosed in childhood. RESULTS: Molecular analyses revealed nine patients had ATP6V0A4 pathogenic variants, five in ATP6V1B1, and two in SLC4A1. A novel intragenic deletion and a common ATP6V0A4 gene variant (c.1691 + 2dupT) in ATP6V0A4 occurred in two-thirds of these patients, suggesting a founder effect. Median age at diagnosis was 3.25 months (IQR 1, 13.5), which was higher in the SLC4A1 group. Median SDS height at diagnosis was -1.02 (IQR -1.79, 0.14). Delayed clinical diagnosis was significantly related to growth failure (P = 0.01). Median SDS height at 20 years follow-up was -1.23 (IQR -1.71, -0.48), and did not significantly improve from diagnosis (P = 0.76). Kidney function declined over time: at last follow-up, 43% had moderate to severe chronic kidney disease (CKD). Adequate metabolic control was not related to CKD development. Incidence of sensorineural hearing loss (SNHL) was high in ATP6V1B1 patients, though not universal. Patients harboring ATP6V0A4 variants also developed SNHL at a high rate (80%) over time. CONCLUSIONS: Patients with dRTA can develop moderate to severe CKD over time with a high frequency despite adequate metabolic control. Early diagnosis ameliorates long-term height prognosis.

Five patients with disorders of calcium metabolism presented with GCM2 gene variants.

The GCM2 gene encodes a transcription factor predominantly expressed in parathyroid cells that is known to be critical for development, proliferation and maintenance of the parathyroid cells. A cohort of 127 Spanish patients with a disorder of calcium metabolism were screened for mutations by Next-Generation Sequencing (NGS). A targeted panel for disorders of calcium and phosphorus metabolism was designed to include 65 genes associated with these disorders. We observed two variants of uncertain significance (p.(Ser487Phe) and p.Asn315Asp), one likely pathogenic (p.Val382Met) and one benign variant (p.Ala393_Gln395dup) in the GCM2 gene in the heterozygous state in five families (two index cases had hypocalcemia and hypoparathyroidism, respectively, and three index cases had primary hyperparathyroidism). Our study shows the utility of NGS in unravelling the genetic origin of some disorders of the calcium and phosphorus metabolism, and confirms the GCM2 gene as an important element for the maintenance of calcium homeostasis. Importantly, a novel variant in the GCM2 gene (p.(Ser487Phe)) has been found in a patient with hypocalcemia.