Dental manifestations of pseudo-vitamin-D deficiency rickets in a paediatric patient

Vitamin D–resistant rickets shows the resistance to vitamin D (Vit-D) therapy, which traditionally works well in cases with deficiency rickets. The signs start appearing as early as in the first month of life and are characterised by the defective mineralisation at the ends of cartilage and bones despite having normal Vit-D levels in the serum. This case report highlights the dental and maxillofacial manifestations in a 3-year-old girl diagnosed with pseudo-Vit-D deficiency rickets. The report also highlights the variations in the dental manifestations of the condition reported in the literature.

Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)2D3 signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)2D3 and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)2D3-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)2D3 responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)2D3-induced translocation of the VDR to the nucleus and 1,25(OH)2D3-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.

Healthcare Transition Preparation in X-Linked Hypophosphatemia

Introduction/Background: X-linked-dominant hypophosphatemia (XLH), formally known as vitamin-D-resistant rickets, is a rare, hereditary, chronic and progressive skeletal disorder, often perceived as a childhood disease only. Its estimated prevalence is 1 in 20,000. The perception that XLH does not require treatment once the growth plates fuse means that many adolescents/young adults (AYA) are lost to follow-up and then seek care for chronic musculoskeletal symptoms, including the consequences of osteomalacia (bone pain, pseudofractures, fractures) during adulthood. There is a need to improve the healthcare transition (HCT) preparation for AYA with XLH and other rare metabolic bone disorders (MBD) to facilitate consistent and effective care throughout the life span and lessen the psychosocial and economic burden associated with these disorders. Methods/Statement of the Problem: HCT timelines, milestones, and educational tools exist for some chronic conditions such as diabetes or kidney disease, but these programs do not meet the unique needs and nuances of patients with XLH and other rare MBD as they transfer to adult-focused healthcare. Consequently, specific tools and resources tailored by disease experts for these AYA are needed. Results/Proposed Solution: Detailed timelines with milestones and a description of a HCT program for AYA with XLH and other rare MBD have been adapted from best practice protocols. This program reflects the specific needs of, and complexities associated with these conditions. Furthermore, this approach describes how to facilitate better communication between adult- and pediatric-focused providers and their interdisciplinary teams. Our approach is guided by patient/caregiver input and existing models for research/clinical care, with the use of validated tools to measure HCT readiness. We identified the need for psychosocial and access-related resources for AYA emancipation from parental involvement, including a guidance document for parents on how to empower their child to take ownership of the disease as they grow. In addition, it is helpful to provide disease education, genetic counselling and guidance on family planning, to encourage patients to advocate for their healthcare (as access to specialists may be limited by geographical location), and to facilitate communication/education to patients through channels familiar to and accepted by AYA (e.g. online portals, text messages). Clear HCT preparation guidelines and treatment-related goals are defined for all stakeholders. A portfolio of supporting materials underpins optimization of outcomes as AYA with XLH and rare MBD transfer from pediatric- to adult-focused healthcare. Conclusion: Development of HCT tools/resources specific to XLH and other rare MBDs can help prevent loss to follow-up and promote continuous clinical care, thus driving better outcomes for AYA with these conditions.

Hereditary vitamin D-resistant rickets: a report of four cases with two novel variants in the VDR gene and successful use of intermittent intravenous calcium via a peripheral route

BackgroundHereditary vitamin D-resistant rickets (HVDRR) is caused by vitamin D receptor (VDR) defects. Patients with HVDRR do not respond to standard doses of calcitriol and oral calcium (Ca) treatment and need to be treated with intravenous Ca (IV-Ca) via a central route. However, central catheter-related complications can cause significant morbidity.Case presentationFour unrelated patients with HVDRR presenting with rickets and alopecia totalis were administered intermittent IV-Ca treatment (2–5 times/week) through a peripheral route. No complications such as infection, extravasation or arrhythmias were detected upon peripheral infusion. Peripheral 1–22 months’ duration of IV-Ca normalized parathyroid hormone (PTH) and alkaline phosphatase (ALP) in all patients, after which, oral Ca of 200–400 mg/kg/day and calcitriol of 0.5 μg/kg/day were sufficient to maintain normal PTH levels. Molecular studies on the VDR gene showed a previously reported homozygous c.454C > T (p.Q152*) pathogenic variant in two patients. Two novel homozygous variants in the other two patients were detected: (1) c.756-2A > G, which affects the splice acceptor site, and (2) c.66dupG (p.I23Dfs*20) variant leading to a frameshift that results in a premature stop codon.ConclusionsPeripheral IV-Ca treatment is an effective and practical alternative treatment mode that provides dramatic clinical benefit in patients with HVDRR.

Cinacalcet treatment experience in hereditary vitamin D resistant rickets

BackgroundHereditary vitamin D resistant rickets (HVDRR) is a bone disorder characterized by a phenotype of rickets with onset at early stage of life with elevated alkaline phosphatase, hypocalcemia, hypophosphatemia, hyperparathyroidism and elevated levels of 1,25-dihydroxyvitamin D (calcitriol) as a consequence of the resistance of the vitamin D receptor (VDR). Mutations in the DNA-binding domain of the VDR of the vitamin D receptor have been characterized by a lack of response to traditional treatment with calcium and calcitriol. Secondary hyperparathyroidism and hypophosphatemia are the main factors in its pathogenesis. Cinacalcet is a calciomimetic drug that reproduces the action of calcium by increasing the sensitivity of the calcium-sensitive receptors (CASR) of the parathyroid glands that regulate the secretion of the parathyroid hormone (PTH).Case presentationWe describe its effectiveness and safety in a patient with HVDRR and review other published report cases in the literature. According to published experience, cinacalcet could be used as an adjunctive treatment for the HVDRR with mutations in the DNA-binding domain of the VDR refractory to traditional treatment. Due to lack of knowledge of possible effects of cinacalcet on CASR in the skeleton, long-term use should be avoided.ConclusionsThe optimal dose of cinacalcet for treatment of HVDRR ranges between 0.25 and 0.5 mg/kg/day. Serious side effects of cinacalcet have not been published in this type of patient, although we considered that a close monitoring is necessary in order to detect hypocalcemia.

Vitamin D-Resistant Rickets Diagnostics and Treatment Challenges at Muhimbili National Hospital, Tanzania

Introduction. Rickets is softening of bones caused by defective mineralization of the cartilage in the epiphyseal growth plate, causing widening of the ends of long bones, growth retardation, and skeletal deformities in children. It can be classified into calciopenic and phosphopenic, each type with various subclasses. Case Presentations. We presented 2 cases, first of a 1 year and 4-month-old male, with a history of recurrent episodes of cough for 8 months and bowing of the legs 6 months prior to admission. Clinical and laboratory investigation was suggestive of vitamin D-dependent rickets, and he started vitamin D treatment with minimal response. The second case is of a 4 years and 7-month-old male who presented with developmental delay, poor weight gain, and recurrent chest infection and worsening of bone pain since 9 months of age. Laboratory investigation was suggestive of phosphopenic rickets, and he was started on treatment at 9 months of age with little improvement and at 4 years, he sustained multiple fractures and succumbed to severe respiratory tract infection and died at 4 years and 7 months of age. Conclusion. Rickets pose a diagnostic and treatment challenge in resource-limited countries, and clinical judgment and early initiation of treatment are important.