Vitamin D-dependent rickets (VDDR) type 1: case series of two siblings with a CYP27B1 mutation and review of the literature / Raquitismo dependente de vitamina D: tipo 1: série de casos de dois irmãos com mutação CYP27B1 e revisão da literatura

Abstract Two siblings presented with clinical and biochemical features of rickets, initially suspected as hypophosphatemic rickets. There was no improvement initially, hence the siblings were reinvestigated and later diagnosed as having vitamin D-dependent rickets (VDDR) type 1 due to a rare mutation in the CYP27B1 gene encoding the 1α-hydroxylase enzyme. Both siblings improved with calcitriol supplementation. The initial presentation of VDDR is often confusing and algorithmic evaluation helps in diagnosis. We also present a brief review of the literature, including genetics.

Resumo Dois irmãos apresentaram características clínicas e bioquímicas do raquitismo, com suspeita clínica inicial de raquitismo hipofosfatêmico. Não houve melhora no início, portanto os irmãos foram reavaliados e, posteriormente, diagnosticados com raquitismo dependente de vitamina D (VDDR) tipo 1 devido a uma rara mutação no gene CYP27B1, que codifica a enzima 1a-hidroxilase. Ambos os irmãos melhoraram com a suplementação de calcitriol. A apresentação inicial do VDDR geralmente é confusa e a avaliação algorítmica ajuda no diagnóstico. Também apresentamos uma breve revisão da literatura, incluindo genética.

Normal physiological functions in two animal species with highly different vitamin d status compared to that of humans / Funciones fisiológicas normales en dos especies animales con estatus de vitamina d muy diferentes del actual en seres humanos

Mole rats live in permanent darkness, in networks of underground tunnels (which extend up to 1 km in the subsoil), excavated with their incisors, in warm and semi-arid areas of South Africa. Mole rats have an unusually impoverished vitamin D3 status with undetectable and low plasma concentrations of 25- hydroxyvitamin D3 and 1α,25-dihydroxyvitamin D3, respectively. They express 25-hydroxylase in the liver and 1-hydroxylase and 24-hydroxylase in their kidneys. The presence of specific receptors (VDR) was confirmed in the intestine, kidney, Harderʼs glands and skin. In spite of their poor vitamin D3 status, the apparent fractional intestinal absorption of calcium, magnesium and phosphate was high, always greater than 90%. Oral supplementation with cholecalciferol to mole rats did not improve the efficiency of gastrointestinal absorption of these minerals. Mole ratsdo not display the typical lesion of rickets: hypertrophic and radiolucent growth cartilages. Histological studies reported normal parameters of trabecular and cortical bone quality. Marmosets (monkeys of the New World) are not hypercalcaemic, eventhough they exhibit much higher levels of 25-hydroxyvitamin D3, 1α,25-dihydroxyvitamin D3 and parathyroid hormonethan that of rhesus monkeys and humans. Fed a high vitamin D3 intake (110 IU/day/100 g of body weight), a fraction of the experimental group was found to display osteomalacic changes in their bones: distinct increases in osteoid surface, relative osteoid volume, and active osteoclastic bone resorption. These findings suggest that some marmosets appears to suffer vitamin D-dependent rickets, type II. The maximum binding capacity of the VDR or the dissociation constant of VDR1α,25(OH)2D3 complex of mole rats and New World monkeys are distinctly different of VDR isolated from human cells. Health status of those species appears to be adaptations to the mutations of their VDR. Though rare, as mutations may occur at any time in any patient, the overall message of this review to clinicians may be: recent clinical studies strongly suggests that the normality of physiological functions might be a better indicator of the health status than the serum levels of vitamin D metabolites. (AU)

Las ratas topo viven en la oscuridad permanente, en redes de túneles subterráneos excavadas con sus incisivos (que se extienden hasta 1 km en el subsuelo), en áreas cálidas y semiáridas de Sudáfrica. Las ratas topo tienen un estatus de vitamina D3 inusualmente empobrecido con concentraciones plasmáticas indetectables de 25-hidroxivitamina D3 y bajas de 1α, 25-dihidroxivitamina D3. Poseen 25-hidroxilasa en el hígado y 1-hidroxilasa y 24-hidroxilasa en sus riñones. La presencia de receptores específicos (VDR) ha sido confirmada en el intestino, el riñón, las glándulas de Harder y la piel. A pesar de su pobre estatus de vitamina D3,la absorción fraccional intestinal aparente de calcio, magnesio y fosfato fue alta, siempre superior al 90%. La suplementación oral con colecalciferol a las ratas topo no mejoró la eficacia de la absorción gastrointestinal de estos minerales. No muestran la lesión típica del raquitismo: cartílagos de crecimiento hipertróficos y radiolúcidos. Varios estudios histológicos confirman los hallazgos radiológicos y se informan parámetros normales de la calidad ósea trabecular y cortical. Los titíes (monos del Nuevo Mundo) exhiben calcemias normales con niveles más elevados de 25-hidroxivitamina D3, 1α,25-dihidroxivitamina D3 y hormona paratiroidea que los monos rhesus y los seres humanos. Un tercio de un grupo de titíes alimentados con una alta ingesta de vitamina D3 (110 I/día/100 g de peso corporal) exhibió cambios osteomalácicos en sus huesos: aumento en la superficie osteoide, volumen osteoide y activa reabsorción osteoclástica. Estos hallazgos sugieren que una fracción de la población de titíes padece raquitismo dependiente de vitamina D, tipo II. Debido a mutaciones ocurridas hace millones de años, las máximas capacidades de ligamiento del VDR o los valores de la constante de disociación del complejo VDR-1α,25(OH)2D3 de las ratas topo o monos del Nuevo Mundo son muy diferentes de los verificables en receptores aislados de células humanas actuales. El mensaje de esta revisión a los médicos clínicos podría ser: varios estudios clínicos recientes indican que la normalidad de las funciones fisiológicas de un paciente es un mejor indicador de su salud que los niveles séricos de los metabolitos de la vitamina D. (AU)

Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface

Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor β (TGF-β), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-β were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA.

La vitamina D: implicaciones en la salud y el embaraza / Vitamin D: implications in health and pregnancy

La vitamina D cobró importancia desde que se descubrió la naturaleza esteroidea y carácter hormonal de uno de sus metabolitos: el calcitriol. Su participación en el mantenimiento de la homeostasis mineral, así como su capacidad para regular la transcripción génica y fomentar la diferenciación celular, han hecho de su estudio tema de gran interés. Los recientes avances en el estudio de la enzima encargada de convertir la 25-hidroxivitamina D en 1.25-dihidroxivitamina D3 (calcitriol), así como la descripción de su mecanismo de acción, han permitido ampliar el conocimiento de los factores reguladores que controlan el equilibrio del sistema endocrino de la vitamina D, y de las implicaciones del calcitriol en la salud en general y en el embarazo en particular.