Tratamiento de hipoparatiroidismo con parathormona recombinante humana [rhPTH(1-84)] / Hypoparathyroidism treated with recombinant human parathyroid hormone [rhPTH(1-84)]

El hipoparatiroidismo (hipoPTH) es una enfermedad infrecuente caracterizada por hipocalcemia y niveles inapropiadamente bajos o ausentes de parathormona. Presentamos el caso de un hombre de 25 años, deportista de alto rendimiento, con antecedente de hipoPTH secundario a tiroidectomía total dos años antes por cáncer papilar multifocal bilateral tiroideo, estadificado como T3 N1b M0, derivado por hipocalcemia sintomática. Presentaba calcemias promedio de 7mg%, síntomas de hipocalcemia en reposo y múltiples internaciones. Inicialmente, se optimizó tratamiento convencional con aporte de calcio vía oral hasta 12g/día, vitamina D y calcitriol, sin mejoría clínica ni bioquímica. Se descartaron malabsorción y complicaciones crónicas de hipoPTH. Se evidenció a través de cuestionario de salud SF-36 disminución de la calidad de vida. Se indicó sustitución con parathormona recombinante humana [rhPTH(1-84)] 50μg/día subcutánea con posterior ascenso a 75μg y reducción progresiva de la medicación por vía oral. Actualmente se encuentra asintomático, sin requerimiento de calcio ni vitamina D, mantiene calcemias de 9mg%, realiza actividad deportiva y demuestra marcada mejoría en la calidad de vida según cuestionario SF-36 (36-Item Short Form Health Survey).

Hypoparathyroidism (HypoPT) is a rare disease characterized by low calcium and inappropriately low circulating parathormone levels. We present the case of a 25-year-old high-performance athlete male, with history of HypoPT after total thyroidectomy for papillary thyroid carcinoma (T3 N1b M0) two years before, who was referred to our clinic for symptomatic hypocalcemia. The patient reported serum calcium average levels of 7mg%, presented symptoms of hypocalcemia at rest and had multiple hospital admissions. First, standard treatment was optimized by calcium supplementation up to 12g/d and active vitamin D, not showing clinical or biochemical improvement. Malabsorption and complications of chronic HypoPT were ruled out. The 36-Item Short Form Health Survey (SF-36) demonstrated an impaired quality of life (QoL). Full-length recombinant human parathyroid hormone [rhPTH(1-84)] therapy was started with 50μg/d subcutaneous, and later adjusted to 75μg/d and the oral treatment gradually decreased. Currently, he is asymptomatic, with serum calcium levels above 9mg%, without receiving oral medication. He performs sports activity and shows marked improvement in quality of life according to SF-36 questionnaire.

Recidiva del hiperparatiroidismo secundario a enfermedad renal crónica en diálisis luego de la paratiroidectomía / Recurrence of secondary hyper¬parathyroidism in dialysis patients after parathyroidectomy

La paratiroidectomía (PTX) es la terapia de elección en el hiperparatiroidismo secundario a enfermedad renal crónica (HPT-ERC) resistente al tratamiento médico. El objetivo del presente estudio fue evaluar el resultado de la PTX a largo plazo y sus factores predictores. Métodos: estudio unicéntrico retrospectivo observacional. Se incluyeron 92 pacientes con HPT-ERC en diálisis, en quienes se realizó la primera PTX en el Hospital Italiano de Buenos Aires entre 2006 y 2015 con seguimiento ≥ 6 meses. Se consideró persistencia del HPTERC con PTH > 300 pg/ml en el semestre posoperatorio, y recidiva con PTH > 500 pg/ml luego. Resultados: edad: 43,6±12,8 años, 50% mujeres, mediana 4,6 años de diálisis, PTH preoperatoria mediana 1639 pg/ml. A 39 se les realizó PTX subtotal (PTXS) y a 53 total con autoimplante (PTXT+AI). Se observó persistencia en 16 pacientes (17,4%). Presentaron recidiva 30 de 76 pacientes con adecuada respuesta inicial (39,5%; IC 95 28,5-50,5). La mediana de tiempo hasta la recidiva fue de 4,7 años (RIC 2,3-7,5). Los pacientes con recidiva presentaron mayor calcemia preoperatoria (mediana 9,9 vs. 9,3 mg/dl, p=0,035; OR ajustado 2,79) y menor elevación de fosfatasa alcalina en el posoperatorio (333 vs. 436 UI/l, p=0,031; OR ajustado 0,99). La recidiva se presentó más frecuentemente luego de la PTXT+AI (48,9%; OR ajustado 4,66), que en la PTXS (25,8%). Conclusiones: el tiempo en diálisis con inadecuado control metabólico constituye el principal factor para la recurrencia del HPT. Se postula que la mayor calcemia preoperatoria está relacionada con un HPT más severo y se asocia a recurrencia. Llamativamente, hallamos menores elevaciones de la fosfatasa alcalina durante el posoperatorio en pacientes con recurrencia. Hipotetizamos que esto pueda asociarse con menor mineralización en el posoperatorio e hiperfosfatemia sostenida, con consecuente estímulo paratiroideo. La menor recurrencia del HPT luego de la PTXS se vincula al sesgo generado en la selección del tipo de cirugía. (AU)

Parathyroidectomy is an effective therapy for refractory secondary hyperparathyroidism (sHPT). Continued dialysis represents risk for recurrent sHPT. The aim of this study was to estimate the proportion of recurrence and determine its predictors. Methods: We conducted a retrospective observational study of 92 adults in chronic dialysis, who underwent their first parathyroidectomy in this center between 2006 and 2015. We considered persistence of sHPT if PTH was > 300 pg/ml during the first postoperative semester, and recurrence if it was > 500 pg/ml afterwards. Results: Age 43.6+-12 y/o, 50% female, 4.6 years on dialysis, median preoperative PTH 1636 pg/ml (IQR 1226-2098). Subtotal parathyroidectomy (sPTX) was performed in 39, Total with autotransplantation (TA-PTX) in 53 patients. Persistence of sHPT occurred in 16 patients; relapse in 30 out of 76 with adequate initially response (39.5%; 95CI 28,5-50,5). Median time to recurrence: 4.7 y. Recurring patients had higher preoperative calcemia (9.9 vs 9.3 mg/dl; adj OR 2.79) and lower postoperative elevation of ALP (333 vs 436 UI/ml; adj OR 0.99). Recurrence presented more frequently in TA-PTX (48.9%; adj OR 4.66) than sPTX (25.8%). Conclusions: Time on dialysis with inadequate metabolic control remains the most important risk factor for sHPT recurrence. Higher preoperative levels of calcemia, related to sHPT severity, are associated with recurrence. Lower elevations of ALP during postoperative period in recurring patients are an interesting finding. We hypothesize that patients with less significant postoperative mineralization may have chronically higher levels of phosphatemia, stimulating parathyroid glands. Fewer recurrence in sPTX is associated to a bias in the procedure selection. (AU)

Therapeutic effects of vitamin D on acetic acid-induced colitis in rats

Abstract Purpose To analyze the effect of calcitriol treatment on acute colitis in an experimental rat model. Methods A total of 24 adult Sprague Dawley albino rats were randomly separated into 3 equal groups: control group (n:8), colitis group (n:8), calcitriol administered group (n:8). A single dose of acetic acid (1 ml of 4% solution) was administered intrarectally to induce colitis. Group 1 was given 1 ml/kg 0.9% NaCl intraperitoneally; rats belonging to Group 2 were administered calcitriol 1 µg/kg for 5 days. Results Plasma tumor necrosis factor alpha, Pentraxin 3, and malondialdehyde levels were significantly lower in the calcitriol administered colitis group than in the standard colitis group (p<0.01). In the Calcitriol group, there was a significant histological improvement in hyperemia, hemorrhage and necrotic areas in the epithelium compared to the placebo group (p <0.000). Conclusion The findings suggest that calcitriol may be an agent that could be used in acute colitis treatment.

Vitamin D in prostate cancer / 亚洲男科学杂志(英文版)

Signaling through the vitamin D receptor has been shown to be biologically active and important in a number of preclinical studies in prostate and other cancers. Epidemiologic data also indicate that vitamin D signaling may be important in the cause and prognosis of prostate and other cancers. These data indicate that perturbation of vitamin D signaling may be a target for the prevention and treatment of prostate cancer. Large studies of vitamin D supplementation will be required to determine whether these observations can be translated into prevention strategies. This paper reviews the available data in the use of vitamin D compounds in the treatment of prostate cancer. Clinical data are limited which support the use of vitamin D compounds in the management of men with prostate cancer. However, clinical trials guided by existing preclinical data are limited.

Cost-effectiveness analysis of paricalcitol versus calcitriol for the treatment of SHPT in dialytic patients from the SUS perspective / Análise de custo-efetividade de paricalcitol versus calcitriol no tratamento do HPTS em pacientes do SUS dialíticos, da perspectiva

Abstract Introduction: Secondary hyperparathyroidism (SHPT) is a consequence of chronic kidney disease. The treatment at the Brazilian Unified Heath System (SUS) is performed with calcitriol, a drug which favors hypercalcemia and/or hyperphosphatemia, hindering the control of SHPT. Another option is paricalcitol, which causes parathormone (PTH) suppression faster than calcitriol, with minor changes in calcium-phosphorus product and calcium and phosphorus serum levels. Objective: This study aims to develop a cost-effectiveness analysis of paricalcitol versus calcitriol for patients in dialytic treatment with SHPT, from the SUS perspective. Methods: A Markov decision model was developed for patients ≥ 50 years old with end stage renal disease in dialytic treatment and SHPT. Quarterly cycles and a lifetime time horizon were considered. Life years (LY) gained were assessed as clinical outcome. Clinical and economic inputs were obtained from systematic literature review and official databases. Costs are presented in Brazilian real (BRL), for the year 2014. Results: In the base case: paricalcitol generated a clinical benefit of 16.28 LY gained versus 14.11 LY gained with calcitriol, total costs of BRL 131,064 and BRL 114,262, respectively, determining an incremental cost-effectiveness ratio of BRL 7,740 per LY gained. The data robustness was confirmed by the sensitivity analysis. Conclusions: According to cost-effectiveness threshold recommended by the World Health Organization for 2013, the treatment of SHPT in patients on dialysis with paricalcitol is cost-effective when compared to calcitriol, from the public healthcare system perspective, in Brazil.

Resumo Introdução: O hiperparatireoidismo secundário (HPTS) é uma consequência da doença renal crônica. O tratamento no SUS é realizado com calcitriol, que favorece a hipercalcemia e/ou hiperfosfatemia, dificultando o controle do HPTS. Uma opção clinicamente relevante é o paricalcitol, que ocasiona a supressão do paratormônio (PTH) de forma mais rápida que o calcitriol e com menores alterações nas taxas séricas de cálcio, fósforo e do produto cálcio-fósforo. Objetivo: Este trabalho tem como objetivo desenvolver uma análise de custo-efetividade de paricalcitol versus calcitriol para pacientes em diálise com HPTS, perspectiva do SUS. Métodos: Foi desenvolvido um modelo de decisão de Markov para a população ≥ 50 anos, com DRC em diálise e HPTS. Foram considerados ciclos trimestrais e um horizonte temporal lifetime. O desfecho clínico avaliado foram os anos de vida ganhos. Dados foram obtidos a partir de revisão sistemática da literatura e bases de dados oficiais. Custos em reais (R$), ano de 2014. Resultados: No caso base: paricalcitol gerou benefício clínico de 16,28 anos de vida ganhos versus 14,11 anos de vida ganhos com calcitriol, custos totais de R$ 131.064 e R$ 114.262, respectivamente. A razão de custo-efetividade incremental de R$ 7.740 por ano de vida salvo. Dados robustos confirmados pela análise de sensibilidade. Conclusão: De acordo com o limiar de custo-efetividade recomendado pela Organização Mundial de Saúde para o ano de 2013, o tratamento de pacientes com HPTS em diálise com paricalcitol é custo-efetivo, comparado ao calcitriol, perspectiva SUS.

Improvement of health-related quality of life and adherence to treatment with calcipotriol-betamethasone dipropionate gel in patients with psoriasis vulgaris

Abstract BACKGROUND: Psoriasis is a common, chronic, recurrent, immune-mediated disorder of the skin and joints. It can have a significant negative impact on the physical, emotional and psychosocial wellbeing of affected patients. OBJECTIVES: To measure improvement in health-related QoL (HRQoL) in Greek patients with psoriasis vulgaris after a month of treatment with calcipotriol-betamethasone dipropionate gel; and evaluate adherence to treatment parameters. METHODS: The study included 394 psoriasis vulgaris patients from 16 private dermatological practices in Greece, all treated with calcipotriol-betamethasone dipropionate gel. They were evaluated at the first visit and after 4 weeks. Moreover, they completed the Dermatology Life Quality Index (DLQI), while other data such as disease severity, subjective symptoms and adherence, were collected. RESULTS: At week 4, the DLQI median was reduced by 3.5 points from the baseline (p<0.001; baseline and week 4 median: 4.5 and 1.0 respectively). Pruritus and sleep disorders also improved (p<0.001). Furthermore, 90.1% of the subjects fully adhered to treatment, with a 97.1% mean level of compliance. CONCLUSIONS: The convincing clinical results, with a distinct improvement in HRQoL, plus the high level of adherence due to its advantageous physical properties, make the calcipotriol-betamethasone dipropionate gel formulation an important, effective and well-tolerated topical therapy to treat psoriasis.

Treatment with 1,25(OH)2D3 induced HDAC2 expression and reduced NF-κB p65 expression in a rat model of OVA-induced asthma

Recent evidence indicates that a deficiency of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) may influence asthma pathogenesis; however, its roles in regulating specific molecular transcription mechanisms remain unclear. We aimed to investigate the effect of 1,25(OH)2D3 on the expression and enzyme activity of histone deacetylase 2 (HDAC2) and its synergistic effects with dexamethasone (Dx) in the inhibition of inflammatory cytokine secretion in a rat asthma model. Healthy Wistar rats were randomly divided into 6 groups: control, asthma, 1,25(OH)2D3 pretreatment, 1,25(OH)2D3 treatment, Dx treatment, and Dx and 1,25(OH)2D3 treatment. Pulmonary inflammation was induced by ovalbumin (OVA) sensitization and challenge (OVA/OVA). Inflammatory cells and cytokines in the bronchoalveolar lavage (BAL) fluid and histological changes in lung tissue were examined. Nuclear factor kappa B (NF-κB) p65 and HDAC2 expression levels were assessed with Western blot analyses and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Enzyme activity measurements and immunohistochemical detection of HDAC2 were also performed. Our data demonstrated that 1,25(OH)2D3 reduced the airway inflammatory response and the level of inflammatory cytokines in BAL. Although NF-κB p65 expression was attenuated in the pretreatment and treatment groups, the expression and enzyme activity of HDAC2 were increased. In addition, 1,25(OH)2D3 and Dx had synergistic effects on the suppression of total cell infusion, cytokine release, and NF-κB p65 expression, and they also increased HDAC2 expression and activity in OVA/OVA rats. Collectively, our results indicated that 1,25(OH)2D3 might be useful as a novel HDAC2 activator in the treatment of asthma.

Topical calcipotriol as a new therapeutic option for the treatment of clear cell acanthoma

Although uncommonly diagnosed, clear cell acanthoma represents an original source of speculative interest for dermatologists. Due to its clinical variability, it is often only recognized accidentally after histology. Dermoscopy has improved the reliability of clinical diagnosis of typical clear cell acanthoma thanks to the vascular pinpoint pattern and desquamative, peripheral collarette. Generally, therapy of clear cell acanthoma is oriented towards ablative solutions, such as surgery or cryotherapy. We propose a conservative therapy, based on the application of topical calcipotriol, which has produced complete regression after 2 months and no relapse one year after the end of treatment. A dermatoscope monitored all changes of clear cell acanthoma, showing its utility not only in diagnosis but also in therapeutic follow-up. This new therapeutic approach should support an inflammatory etiology of clear cell acanthoma, although further observations are needed to confirm this.

Newer targeted therapies in psoriasis.

Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted due to chronicity of the disease and frequent remissions and relapses. Many available systemic therapies, however, are unsuitable for chronic administration due to the risk of cumulative toxicity. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. These include approaches targeting antigen presentation and co-stimulation, T-cell activation and leukocyte adhesion, action on pro-inflammatory mediators, and modulating the cytokine balance. Although only preliminary data are available so far and there is limited data supporting their use, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis.

Newer targeted therapies in psoriasis.

Psoriasis is a common, chronic, inflammatory skin disease that can have a significant impact on the quality of life of those who are afflicted due to chronicity of the disease and frequent remissions and relapses. Many available systemic therapies, however, are unsuitable for chronic administration due to the risk of cumulative toxicity. Recent advances in the understanding of the pathophysiology of psoriasis have led to the development of new, genetically engineered, targeted therapies for this disease. These include approaches targeting antigen presentation and co-stimulation, T-cell activation and leukocyte adhesion, action on pro-inflammatory mediators, and modulating the cytokine balance. Although only preliminary data are available so far and there is limited data supporting their use, these trials contribute to a further understanding of the disease and will eventually lead to new therapeutic options for psoriasis.

A Case of Isolated Small Intestinal Wall Calcification on Patient with Continuous Ambulatory Peritoneal Dialysis / 대한소화기학회지

The metastatic calcification is defined as the deposition of calcium salt in normal tissue with an abnormal serum biochemical environment, such as chronic kidney disease, hyperparathyroidism, and hypercalcemia related with malignancy. Although the metastatic calcification can develop in any organs and tissues, presenting its symptoms and complications are rare. Thus a few cases have been reported. This case shows the metastatic calcification of the small intestine without any peritoneal and mesenteric vascular calcification which was early diagnosed by computed tomography and mesenteric angiography in a patient with abdominal pain, receiving continuous ambulatory peritoneal dialysis due to end stage renal disease. The clinician should early consider the metastatic calcification as differential diagnosis when unidentified calcifications are noted in simple abdominal X-ray such as in the present case, and promptly confirm it by using appropriate diagnostic tests in order to prevent its complications and progression.

Daivobet(calcipotriol+dipropionato de betametasona) para o tratamento da psoríase / Daivobet (calcipotriol + betamethasone dipropionate) for the treatment of psoriasis

A psoríase é uma das doenças inflamatórias da pele mais frequentes do mundo. Caracteriza-se por lesões eritêmato-descamativas com padrões e distribuição corpórea variáveis, podendo ser classificada fenotipicamente em formas vulgar, gutata, eritrodérmica e pustulosa. A forma mais frequente da psoríase é a psoríase em placas ou vulgar. O número, dimensão e extensão das lesões são variáveis entre os pacientes e conforme a evolução da doença. As lesões surgem sobretudo nos cotovelos, joelhos, região lombar e couro cabeludo, embora possam afetar qualquer área do corpo, cobrindo, nos casos mais graves, extensas áreas do tronco e membros. O Daivobet® é uma combinação de duas substâncias com diferentes mecanismos de ação: hidrato de calcipotriol, um análogo da vitamina D3, com ação anti-proliferativa; e dipropionato de betametasona, um corticosteroide tópico, com potente ação anti-inflamatória. Como existe uma incompatibilidade química entre o calcipotriol e os corticóides de alta potência, não é recomendado que se misture os dois produtos finais. A incompatibilidade se deve ao fato de que o calcipotriol necessita de um alto pH para ter estabilidade e o dipropionato de betametasona só é estável em meio ácido (pH em torno de 3,5). Um veículo inovador permite a combinação dos dois princípios ativos na mesma formulação com garantia da estabilidade dos dois componentes. A evidência atualmente disponível sobre a eficácia do Daivobet® individualmente é limitada, mas como grupo farmacológico (análogo de vitamina D + corticosteróide) fica demonstrado sua eficácia clínica para tratamento tópico da psoríase vulgar, apesar de que esta eficácia é, em algumas circunstâncias, de pouco impacto clínico dependendo do desfecho analisado e do tipo de comparador avaliado. Também temos que ter em consideração a gravidade e o grau de comprometimento do paciente, que como foi observado em outros estudos, os melhores resultados foram obtidos em pacientes com Psoríase Leve, indicação que também é recomendada pelo Consenso Brasileiro de Psoríase. Os membros da CONITEC presentes na reunião ordinária do dia 02/08/2012, por unanimidade, deliberaram por recomendar a não incorporação do medicamento Daivobet® (calcipotriol + dipropionato de betametasona) para o tratamento da psoríase. Foi assinado o Registro de Deliberação nº 15/2012 na 7ª reunião ordinária de 02/08/2012.

Cost-effectiveness analysis regarding postoperative administration of vitamin-D and calcium after thyroidectomy to prevent hypocalcaemia / Análisis de costo-efectividad de la administración postoperatoria de Vitamina D y calcio después de tiroidectomía para la prevención de la hipo calcemia

Objective Hypocalcaemia is a frequently arising complication following total thyroidectomy. Routine postoperative prophylactic administration of vitamin D or metabolites and calcium reduce the incidence of symptomatic hypocalcaemia; this article reports evaluating its cost-effectiveness in Colombia. Methods Meta-analysis was used for comparing the administration of vitamin D or metabolites to oral calcium or no treatment at all in patients following total thyroidectomy and a cost-effectiveness analysis was designed based on a decision-tree model with local costs. Results The OR value for the comparison between calcitriol and calcium compared to no treatment and to exclusive calcium treatment groups was 0.32 (0.13-0.79 95 %CI) and 0.31 (0.14-0.70 95 %CI), respectively. The most cost-effective strategy was vitamin D or metabolites and calcium administration, having a US $0.05 incremental cost-effectiveness ratio. Conclusion Prophylactic treatment of hypocalcaemia with vitamin D or metabolites + calcium or calcium alone is a cost-effective strategy.

Objetivos La hipo calcemia es la complicación más frecuente después de tiroidectomía. La administración profiláctica de vitamina D o metabolitos y calcio reduce la incidencia de hipocalcémia sintomática. Se evalúa su costo-efectividad en Colombia. Materiales y métodos Utilizamos la información de un meta-análisis que comparó la administración de vitamina D o metabolitos contra calcio no tratamiento en pacientes llevados a tiroidectomía total y diseñamos un análisis de costo-efectividad basados en un modelos de decisiones con costos locales. Resultados El valor del OR para la comparación entre calcitriol y calcio comparado con no tratamiento o calcio exclusivo fue de 0.32 (95 % IC, 0.13- 0.79) y 0.31 (95 % IC, 0.14-0.70), respectivamente. La estrategia más costo-efectiva fue la administración de vitamina D o metabolitos y calcio, con una relación de costo-efectividad incremental de US $0.05. Conclusiones El tratamiento profiláctico de la hipo calcemia con vitamina D o metabolitos y calcio o calcio exclusivo después de tiroidectomía total es una estrategia costo-efectiva.

Vitamina D y cáncer / Cancer and vitamin D

El cáncer es una de las mayores causas de muerte en el mundo. Si bien la vitamina D (colecalciferol) ha sido asociada a la regulación de la homeostasis de calcio, muchos son los datos epidemiológicos, bioquímicos y genéticos sobre otros efectos importantes de la vitamina D, como el desarrollo y la progresión de diferentes cánceres. El objetivo del presente artículo es revisar distintos aspectos acerca de los mecanismos de acción y efectos moleculares de la vitamina D o sus metabolitos y de los indicadores epidemiológicos que los correlacionan con el cáncer, su prevención y tratamiento. El estudio de los efectos de la vitamina D se ha vuelto muy amplio: nuevos genes, nuevos blancos, mecanismos diferentes. Niveles adecuados de vitamina D son necesarios para una gran cantidad de procesos fisiológicos y no solamente para el mantenimiento de la homeostasis del calcio. Los estudios clínicos podrían revisar las recomendaciones sobre las dosis de vitamina D que puedan proteger también contra el desarrollo del cáncer.

Mutations in the vitamin D receptor gene in four patients with hereditary 1, 25-dihydroxyvitamin D-resistant rickets / Mutações no gene do receptor de vitamin D em quatro pacientes com raquitismo hereditário resistente a 1, 25-dihydroxyvitamin D

Mutations in the vitamin D receptor (VDR) are associated to the hereditary 1,25-dihydroxivitamin D-resistant rickets. The objectives of this work are: search for mutations in the VDR and analyze their functional consequences in four Brazilian children presented with rickets and alopecia. The coding region of the VDR was amplified by PCR e direct sequenced. We identified three mutations: two patients had the same mutation in exon 7 at aminoacid position 259 (p.Q259E); one patient had a mutation in exon 8 at codon 319 (p.G319V) and another one had a mutation in exon 3 leading to a truncated protein at position 73 (p.R73X). Functional studies of the mutant receptors of fibroblast primary culture, from patients' skin biopsy treated with increasing doses of 1,25(OH)2 vitamin D showed that VDR mutants were unable to be properly activated and presented a reduction in 24-hydroxylase expression level.

Mutações no receptor de vitamina D (VDR) são associadas a raquitismo hereditário resistente a 1,25-dihidroxivitamina D. Os objetivos deste trabalho foram procurar mutações no VDR e analisar suas conseqüências funcionais em quatro pacientes com raquitismo e alopécia. A região codificadora do VDR foi amplificada por PCR e seqüenciada diretamente. Identificamos três mutações: dois pacientes apresentavam a mesma mutação no éxon 7 na posição protéica 259 (p.Q259E); um paciente apresentava uma mutação no éxon 8 no códon 319 (p.G319V) e o outro apresentava uma mutação no exon 3 resultando em uma proteína truncada na posição 73 (p.R73X). O estudo funcional dos receptores mutados nos extratos de culturas de fibroblasto primárias obtidas de biópsia de pele dos pacientes, tratados com doses crescentes de 1,25(OH)2 vitamina D demonstraram que os receptores mutantes não apresentam ativação adequada apresentando expressão reduzida de 24-hidroxilase.