Vitamin D-Dependent Rickets Type 3: A Case Report and Systematic Review.

Although vitamin D deficiency resulting from insufficient sunlight exposure or inadequate dietary vitamin D intake is the most common cause of rickets, mutations in genes involved in vitamin D metabolism can cause genetic forms of rickets termed Vitamin D-Dependent Rickets (VDDR). In 2018, Roizen et al. described a new type of VDDR, named VDDR3, caused by a recurrent missense mutation in the CYP3A4 gene that leads to accelerated inactivation of vitamin D metabolites. Here, we describe the third case of VDDR3 due to the same CYP3A4 mutation in a 2-year-old boy with bone deformities associated with poor growth. As in the previously reported cases, this patient had no family history of rickets. Serial measurements of vitamin D metabolites after a single 150,000 IU dose of cholecalciferol demonstrated an accelerated inactivation of 25(OH)D and 1,25(OH)2D. Significant improvement in growth velocity and healing of bone deformities were achieved after a short period of treatment with 10.000 IU of cholecalciferol daily, showing the importance of early recognition and prompt precision therapy of this condition.

Vitamin D metabolism and extraskeletal outcomes: an update.

Vitamin D deficiency is a general health problem affecting individuals at all stages of life and on different continents. The musculoskeletal effects of vitamin D are well known. Its deficiency causes rickets, osteomalacia, and secondary hyperparathyroidism and increases the risk of fractures. Clinical and experimental evidence suggests that vitamin D performs multiple extraskeletal functions. Several tissues unrelated to calcium and phosphate metabolism express vitamin D receptor (VDR) and are directly or indirectly influenced by 1,25(OH)2D (calcitriol). Some also express the enzyme 1 alpha-hydroxylase (CYP27B1) and produce 1,25(OH)2D, inducing autocrine or paracrine effects. Among the pleiotropic effects of vitamin D are the regulation of cell proliferation and differentiation, hormone secretion, and immune function. In this review, we outline vitamin D physiology and the outcomes of recent large RCTs on its potential extraskeletal effects. Those studies exhibit a need for continued clinical analysis to elucidate whether vitamin D status can influence extraskeletal health. Longer longitudinal follow-up and standardized assays are crucial to better assess potential outcomes.

Osteoporosis in swine / Osteoporose em suínos

Forty-six pigs presented muscle weakness, hind limb paresis and paralysis, weight loss, lateral recumbency, and death in a clinical course of 7 to 10 days. Two pigs were necropsied and exhibited bone fragility, bone callus formation, and multiple fractures in the limbs, ribs, and vertebrae. Microscopically, there was a diffuse and marked decrease in thickness and number of trabeculae. These were disconnected, with a "free-floating" appearance, while the cortex of the long bones was thinned, with an increase of the cortical porosity by enlargement of Haversian canals and endosteal erosion and decreased osteoblastic activity. Flame atomic absorption spectrometry in liver samples revealed significant zinc overload (>2300ppm) and copper deficiency (<33.1ppm). In this communication, we present the first pathologic description of an outbreak of osteoporosis in pigs, and we also provide a brief review of metabolic bone diseases in pigs.

Quarenta e seis suínos apresentaram fraqueza muscular, paresia e paralisia de membros pélvicos, perda de peso, decúbito lateral e morte, com um curso clínico de 7 a 10 dias. Dois suínos foram submetidos a necropsia e exibiram fragilidade óssea, formação de calo ósseo, e múltiplas fraturas em membros, costelas e vértebras. Microscopicamente notou-se difusamente um marcado decréscimo na espessura e número de trabéculas ósseas. Essas estavam desconexas, com uma aparência de flutuação, enquanto o córtex dos ossos longos estava afinado, com um aumento da porosidade pela dilatação dos canais de Haversian, erosão endosteal e diminuição da atividade osteoblástica. Espectrofotometria por chama foi realizada em amostras de fígado, e revelou um excesso de zinco (>2300ppm) e deficiência de cobre (<33.1ppm). Neste trabalho, apresentamos a primeira descrição patológica de um surto de osteoporose em suínos, além de fornecer uma breve revisão de doenças metabólicas em suínos.

La accidentada historia del descubrimiento de la vitamina D, en su primer centenario / The checkered history of the discovery of vitamin D, in its first centenary

El año 2022 marca el primer centenario del descubrimiento de la vitamina D, hallazgo que recompensó la prolongada búsqueda de la causa del raquitismo, su prevención y tratamiento. Al mismo tiempo puso en marcha importantes investigaciones relaciona-das con su biotransformación y el mecanismo de su acción antirraquítica, además de estudios sobre diversos efectos biológicos sin relación directa con su papel en la salud ósea. Esta breve revisión se limitará a delinear la prehistoria de la vitamina D y los diversos estudios, básicos y clínicos, que condujeron a su descubrimiento y caracterización química. (AU)

The year 2022 marks the centenary of the discovery of vitamin D, a breakthrough that rewarded the long search for the cause of rickets, its prevention and treatment. At the same time, it launched important investigations related to its biotransformation and the mechanism of its antirachitic action, as well as studies on various biological effects without direct relation to its role in bone health. This brief review will be limited to an outline of the prehistory of vitamin D and the various basic and clinical studies that led to its discovery and chemical characterization. (AU)

Safety and effectiveness of vitamin D mega-dose: A systematic review.

INTRODUCTION: Supplementation with high doses of vitamin D, known as mega-dose or "stoss therapy," refers to administering high doses of vitamin D by oral or intramuscular route in short periods of time. In this sense, conducting a review to organize this knowledge in a single article will generate a helpful instrument for researchers working in this area and for health professionals who use this therapeutic tool. OBJECTIVE: To carry out a literature review on safety and efficacy (normalization of serum vitamin D level, and changes in the clinical picture) of vitamin D mega-dose use. METHODOLOGY: This is a systematic review of the literature searching data through the electronic banks of PubMed, Scielo, and LILACS, using the following keywords: "vitamin D," "mega-dose," "stoss therapy," "cholecalciferol," in different combinations. CONSORT questionnaire was used to assess the quality of the included studies. RESULTS: Of the 59 articles screened for this review, 10 were included in the review, studying patients with rickets, osteoporosis, and critically ill patients. Two studies compared the exact dosage of vitamin D by different routes of administration, and three studies compared different doses by the same route. All others studied vitamin D mega-dose versus placebo. Adverse effects were observed through the presence of hypercalcemia/hypercalciuria. Serum vitamin D levels were normalized between 70 and 100% of patients, and adverse effects ranged between 1.9 and 18.5%. CONCLUSION: The study demonstrated that vitamin D mega-dose therapy is effective in normalizing serum vitamin levels, and the toxicity assessed through adverse effects was low, with no expressive clinical significance. Despite this, there is still a need for further studies in the area to confirm the results found.

[Rickets associated to the use of elemental formula: A case report]. / Raquitismo vinculado al uso de fórmulas elementales: Reporte de caso.

The rickets is a disease that affects the differentiation and mineralization of the growth cartilage, as an ultimate consequence of a balance loss in calcium and phosphate levels. Vitamin D deficiency is the most common cause of the rickets (nutritional rickets). Its clinical manifestation during the first years of life involves long bones epiphysis in a more severe way. We report an 8-month-old infant who was diagnosed with cow´s milk protein allergy and suffered from multiple fractures while receiving elemental formula as part of his treatment. The final etiology was hypophosphatemic rickets secondary to phosphate deficiency, and after 3 months of phosphate, calcium and calcitriol supplementation, in addition to the gradually reduction of the proportion of elemental formula intake and the decline of the antacid doses, clinical and radiological heal was achieved.

El raquitismo afecta la diferenciación y mineralización del cartílago de crecimiento como consecuencia, en última instancia, de una alteración en los niveles de fósforo y/o calcio. El secundario a la deficiencia de vitamina D es la forma más frecuente (raquitismo carencial). Las manifestaciones clínicas durante los primeros años de vida suelen comprometer en forma más marcada las epífisis de los huesos. Se describe el caso de un lactante de 8 meses con diagnóstico de alergia a la proteína de la leche de vaca que presentó múltiples fracturas patológicas mientras se encontraba bajo tratamiento con fórmulas lácteas a base de aminoácidos. Se efectuó el diagnóstico de raquitismo hipofosfatémico por deficiencia de fósforo y, tras 3 meses de tratamiento con sales de fosfato, calcio, calcitriol, el abandono paulatino de la leche elemental y el descenso gradual de la medicación antiácida, el paciente evolucionó con curación clínico-radiológica del cuadro.

Arte, historia y endocrinología / Art, history and endocrinology

Las enfermedades han sido representadas en el arte desde tiempos remotos. Las obras pictóricas muchas veces nos muestran trastornos que aún no se constituían como una entidad. Observar estos cuadros a la luz de la historia de las enfermedades nos da una perspectiva enriquecedora que nos ayuda a entender mejor dichas patologías. Se comenta un caso clínico endocrinológico pediátrico, la historia probable y su descripción física. Se revisa la historia de cómo se llegó a dilucidar la enfermedad y las claves de su tratamiento.

Diseases have been represented in art since ancient times. Paintings often show us disorders that had not yet been described as a pathological entity. Looking at these pictures in the light of the history of the diseases gives us an enriching perspective that helps us to better understand those pathologies. On this background a pediatric endocrinological clinical case, the most probable history and the features of the physical examination are discussed. The history of how the disease was uncovered and the keys of its treatment are reviewed.

Outbreak of rickets in pigs in the west of Santa Catarina

Background: Rickets is a deficiency pathology that occurs in young and growing animals, leading to deficient bone mineralization. Rickets has been reported in several species producing numerous economic losses. The disease is caused by nutritional imbalance of calcium (Ca), phosphorus (P) and vitamin D. The aim of this work was to report two outbreaks of rickets in commercial weaning farms in the Seara city, in the western region of Santa Catarina State (SC), Brazil. Case: In August 2016, the Veterinary Pathology Laboratory (LPV) at the Concórdia Campus of the Catarinense Federal Institute (IFC) diagnosed two outbreaks of rickets in pigs in the weaning phase in Seara, SC. The clinical history was obtained by interviewing the field veterinarian and the farmers. In the anamnesis, both pig farmers stated having used a feed premix product from the same company, starting three months ago, and after that the pigs presented clinical signs of posterior paralysis and progressive weight loss. Six animals were submitted to necropsy and organs were collected from the abdominal and thoracic cavities; central nervous system and bones; fixed in 10% buffered formalin, routinely processed, paraffin embedded and stained with hematoxylin and eosin (HE) for histopathological analysis. Bone specimens were decalcified in nitric acid working solution 20 times their volume, during 5 days. In addition, samples of the premix product containing minerals and vitamins were sent to a specialized laboratory to analyze macroelements levels through the atomic absorption methodology. In property 1, there was a batch of 100 animals, the morbidity rate was 15% and lethality was 5%. In property 2, among 30 animals, the morbidity and lethality rate were 33%. Five animals from property 1 and one...(AU)

Rickets in white-eared opossums (Didelphis albiventris) / Raquitismo em gambás-de-orelha-branca (Didelphis albiventris)

Two young opossums were necropsied and diagnosed with rickets. This study aims to describe the clinical-pathological aspects of rickets in Didelphis albiventris. Macroscopically, the opossums presented kyphosis and scoliosis, lateral deviation of the limbs in varus, locomotion difficulty, and enlargement with softening of costochondral junctions (rickety rosary). Samples of bones and joints were processed for hematoxylin and eosin staining and Masson's trichrome. Microscopically, we observed thickening of the epiphyseal plate, characterized by irregular and multifocal proliferation of serialized and hypertrophic cartilage zones, which formed circular groups of large, dysplastic chondrocytes towards the spongy zone, often surrounded by non-mineralized osteoid tissue. In the cortical bone, there were pale eosinophilic zones around the Havers channels consistent with non-mineralized osteoid. The staining of Masson's trichrome evidenced the accumulation of osteoid tissue in cortical and trabecular bones. It is possible that a mixed cause of absorption deficiency of vitamin D3 associated with an unbalanced Ca:P diet based on lactose-free milk and fruits may have triggered the disease.(AU)

Dois gambás jovens foram necropsiados e diagnosticados com raquitismo. O objetivo do trabalho é descrever os aspectos clínico-patológicos de raquitismo em Didelphis albiventris. Macroscopicamente os gambás apresentaram cifose e escoliose, desvio lateral dos membros em varus, dificuldade de locomoção e alargamento com amolecimento das junções costocondrais (rosário raquítico). Amostras dos ossos e articulações foram processadas para coloração de hematoxilina e eosina e Tricrômico de Masson. Microscopicamente havia espessamento da placa epifisária, caracterizada pela proliferação irregular e multifocal das zonas de cartilagem seriada e hipertrófica, que formavam grupos circulares de condrócitos grandes, displásicos em direção a zona esponjosa frequentemente cercados por tecido osteoide não mineralizado. No osso cortical haviam zonas eosinofílicas pálidas ao redor dos canais de Havers consistentes com osteoide não mineralizado. A coloração de Tricrômico de Masson evidenciou o acúmulo de tecido osteoide no nosso cortical e trabecular. Acredita-se que uma causa mista de déficit de absorção de vitamina D3 associada a uma dieta desbalanceada em Ca:P a base de leite sem lactose e frutas tenha desencadeado a doença.(AU)

Rickets in white-eared opossums (Didelphis albiventris) / Raquitismo em gambás-de-orelha-branca (Didelphis albiventris)

Two young opossums were necropsied and diagnosed with rickets. This study aims to describe the clinical-pathological aspects of rickets in Didelphis albiventris. Macroscopically, the opossums presented kyphosis and scoliosis, lateral deviation of the limbs in varus, locomotion difficulty, and enlargement with softening of costochondral junctions (rickety rosary). Samples of bones and joints were processed for hematoxylin and eosin staining and Masson's trichrome. Microscopically, we observed thickening of the epiphyseal plate, characterized by irregular and multifocal proliferation of serialized and hypertrophic cartilage zones, which formed circular groups of large, dysplastic chondrocytes towards the spongy zone, often surrounded by non-mineralized osteoid tissue. In the cortical bone, there were pale eosinophilic zones around the Havers channels consistent with non-mineralized osteoid. The staining of Masson's trichrome evidenced the accumulation of osteoid tissue in cortical and trabecular bones. It is possible that a mixed cause of absorption deficiency of vitamin D3 associated with an unbalanced Ca:P diet based on lactose-free milk and fruits may have triggered the disease.(AU)

Dois gambás jovens foram necropsiados e diagnosticados com raquitismo. O objetivo do trabalho é descrever os aspectos clínico-patológicos de raquitismo em Didelphis albiventris. Macroscopicamente os gambás apresentaram cifose e escoliose, desvio lateral dos membros em varus, dificuldade de locomoção e alargamento com amolecimento das junções costocondrais (rosário raquítico). Amostras dos ossos e articulações foram processadas para coloração de hematoxilina e eosina e Tricrômico de Masson. Microscopicamente havia espessamento da placa epifisária, caracterizada pela proliferação irregular e multifocal das zonas de cartilagem seriada e hipertrófica, que formavam grupos circulares de condrócitos grandes, displásicos em direção a zona esponjosa frequentemente cercados por tecido osteoide não mineralizado. No osso cortical haviam zonas eosinofílicas pálidas ao redor dos canais de Havers consistentes com osteoide não mineralizado. A coloração de Tricrômico de Masson evidenciou o acúmulo de tecido osteoide no nosso cortical e trabecular. Acredita-se que uma causa mista de déficit de absorção de vitamina D3 associada a uma dieta desbalanceada em Ca:P a base de leite sem lactose e frutas tenha desencadeado a doença.(AU)

Rickets in a crab-eating fox (Cerdocyon thous)

Background: Calcium is essential for the healthy development of animals, especially regarding bone formation. Diversefactors influence calcium metabolism, and failure in any of these points may result in metabolic bone diseases. Ricketsis an uncommon disease of growing bones occurring exclusively in young animals, it is characterized by the failure ofosteoid to calcify and can be a result of lack of vitamin D, imbalance of calcium and phosphorus or hereditary conditions.Nutritional origin is more frequent in veterinary medicine, but it has become rarer after the availability of balanced commercial rations. This report describes the diagnosis and treatment of rickets in a crab-eating fox puppy.Case: A 3-month-old male crab-eating fox was presented with ataxia and angular deviation of the tibia and radius/ulnawith suspected osteometabolic disease. It was part of a group of three orphan siblings hand-raised. The other two siblingsdid not present any clinical signs. All three animals presented pale mucous membranes and were infected by ancylostoma,coccidia, toxocara, and sarcocystis. Radiographic findings of the affected animal showed generalized osteopenia of theentire skeleton associated with widening radiolucent distal physeal plates and cupping of the metaphysis, changes classical of rickets. The other two siblings presented no skeletal alterations and complete blood count and biochemistry of allthree animals were taken for comparison, including serum vitamin D and PTH. All three animals presented lymphopenia(5.4-9.3 x 103/uL, reference range 10.3-16.5 x 103/uL), hypoproteinemia (5.1-5.3 g/dL, reference range 5.9-8.2 g/dL),low levels of creatinine (0.4-0.6 mg/dL, reference range 0.7-1.2 mg/dL), increased ALP (181-285 U/L, reference range209.7-267 U/L) and CK (421-500 U/L, reference range for domestic dogs 16-140 U/L). The affected fox presented ionizedcalcium (10.9 mg/dL, reference range for domestic dogs 9.3-11.5 mg/dL) and vitamin...(AU)

Vitamin D Toxicity / Toxicidade da Vitamina D

Abstract Fortification of food products with vitamin D was central to the eradication of rickets in the early parts of the 20th century in the United States. In the subsequent almost 100 years since, accumulating evidence has linked vitamin D deficiency to a variety of outcomes, and this has paralleled greater public interest and awareness of the health benefits of vitamin D. Supplements containing vitamin D are now widely available in both industrialized and developing countries, and many are in the form of unregulated formulations sold to the public with little guidance for safe administration. Together, this has contributed to a transition whereby a dramatic global increase in cases of vitamin D toxicity has been reported. Clinicians are now faced with the challenge of managing this condition that can present on a spectrum from asymptomatic to acute life-threatening complications. This article considers contemporary data on vitamin D toxicity, and diagnostic and management strategies relevant to clinical practice.

Resumo A suplementação de produtos alimentares com vitamina D foi fundamental para a erradicação do raquitismo no início do século XX nos Estados Unidos. Nos quase 100 anos subsequentes, o acúmulo de evidências vinculou a deficiência de vitamina D a uma variedade de desfechos, e isso tem levantado grande interesse público e conscientização dos benefícios à saúde da vitamina D. Os suplementos que contêm vitamina D estão agora amplamente disponíveis tanto nos países desenvolvidos quanto naqueles em desenvolvimento, e muitos estão na forma de formulações não regulamentadas, vendidas ao público com poucas orientações para uma administração segura. Juntos, isso contribuiu para uma transição na qual um aumento global dramático nos casos de toxicidade da vitamina D tem sido relatado. Médicos agora enfrentam o desafio de tratar essa condição que pode apresentar um espectro de complicações assintomáticas a agudas, com risco de vida. Este artigo considera dados atualizados sobre a toxicidade da vitamina D e estratégias de diagnóstico e manejo relevantes para a prática clínica.

Vitamin D Toxicity.

Fortification of food products with vitamin D was central to the eradication of rickets in the early parts of the 20th century in the United States. In the subsequent almost 100 years since, accumulating evidence has linked vitamin D deficiency to a variety of outcomes, and this has paralleled greater public interest and awareness of the health benefits of vitamin D. Supplements containing vitamin D are now widely available in both industrialized and developing countries, and many are in the form of unregulated formulations sold to the public with little guidance for safe administration. Together, this has contributed to a transition whereby a dramatic global increase in cases of vitamin D toxicity has been reported. Clinicians are now faced with the challenge of managing this condition that can present on a spectrum from asymptomatic to acute life-threatening complications. This article considers contemporary data on vitamin D toxicity, and diagnostic and management strategies relevant to clinical practice.