Form Of Rickets Research Articles

Diagnosis, treatment, and management of rickets: a position statement from the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology.

Rickets results from impaired mineralization of growing bone due to alterations in calcium and phosphate homeostasis. Clinical signs of rickets are related to the age of the patient, the duration of the disease, and the underlying disorder. The most common signs of rickets are swelling of the wrists, knees or ankles, bowing of the legs (knock-knees, outward bowing, or both) and inability to walk. However, clinical features alone cannot differentiate between the various forms of rickets. Rickets includes a heterogeneous group of acquired and inherited diseases. Nutritional rickets is due to a deficiency of vitamin D, dietary calcium or phosphate. Mutations in genes responsible for vitamin D metabolism or function, the production or breakdown of fibroblast growth factor 23, renal phosphate regulation, or bone mineralization can lead to the hereditary form of rickets. This position paper reviews the relevant literature and presents the expertise of the Bone and Mineral Metabolism Group of the Italian Society of Pediatric Endocrinology and Diabetology (SIEDP). The aim of this document is to provide practical guidance to specialists and healthcare professionals on the main criteria for diagnosis, treatment, and management of patients with rickets. The various forms of rickets are discussed, and detailed references for the discussion of each form are provided. Algorithms to guide the diagnostic approach and recommendations to manage patients with rare forms of hereditary rickets are proposed.

A case of vitamin-D dependent type-1A rickets

Abstract Rickets is a disease of growing bones characterized by softening of bones as a result of defective mineralization of cartilage in the epiphyseal growth plate. The predominant cause is a deficiency or impaired metabolism of vitamin D. Some forms of rickets do not respond to regular doses of cholecalciferol, which leads to suspicion of vitamin D-dependent rickets (VDDR). VDDR is of two types: type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase, and type II is due to end-organ resistance to the active metabolite of vitamin D. Here, we describe a child with seizures and calcipenic rickets with biochemical profile suggestive of VDDR type 1 worsened by phenytoin which responded completely to calcium and calcitriol supplementation. Whole exome sequencing revealed a heterozygous missense mutation in exon 7 of the TRPV4 gene (chromosome 12,c.1292C>A), whereas no mutations in CYP2R1, CYP27B1, VDR, and CYP3A4 were detected.

Alkaline phosphatase in clinical practice in childhood: Focus on rickets.

Serum alkaline phosphatase (ALP) and its isoenzymes reflect bone metabolism: ALP increases the ratio of inorganic phosphate to pyrophosphate systemically and facilitates mineralization as well as reduces extracellular pyrophosphate concentration, an inhibitor of mineral formation. On the contrary, low ALP activity is associated with reduction of bone turnover. ALP includes four isoenzymes depending on the site of tissue expression: intestinal ALP, placental ALP, germ cell ALP and tissue nonspecific ALP or liver/bone/kidney ALP. The bone isoenzyme (B-ALP) is involved in bone calcification and is a marker of bone turnover as a result of osteoblastic activity. ALP and its isoenzymes are crucial in the diagnostic process of all the forms of rickets.The most common cause of rickets is vitamin D nutritional deficiency. The aim of this review is to update on the role played by ALP serum concentrations as a relevant marker in thediagnosis and treatment of rickets. Indeed, the diagnosis of rickets is based on its clinical, radiological and laboratory characteristics. An elevated ALP level is one of the markers for the diagnosis of rickets in children, though it is also associated with bone formation process. ALP is also useful for the differentiation between rickets and other disorders that can mimic rickets because of their clinical and laboratory characteristics, and, together with other biochemical markers, is crucial for the differential diagnosis of the different forms of rickets. Age, severity and duration of rickets may also modulate ALP elevation. Finally, ALP measurements are useful in clinical and therapeutic follow-up.

Evaluation of the elemental composition of bone tissue in children with genetically determined forms of rickets during treatment

Using neutron activation analysis, we determined the absolute values ​​and ratios of the concentrations of calcium, phosphorus, magnesium, sodium, potassium and chlorine in biopsies of the iliac wing in 20 children with genetically determined forms of rickets (GOFR) before and after drug treatment, as well as in 13 conditionally healthy children (control group). It has been shown that in children with GOFR, the content of calcium, phosphorus, sodium and more than 45% content of magnesium is statistically significantly reduced in comparison with the age norm by an average of 25-30%. Also revealed shifts in the ratio of the concentrations of Ca: Mg, Ca: Na and P: Na. Drug treatment in most children with GOFR leads to the normalization of all studied characteristics, with the exception of magnesium, the deficiency of which is manifested both in the absolute value of its content and in the ratio of Ca: Mg concentrations, which may indicate the need to include medicinal preparations containing magnesium

Rickets guidance: part II—management

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.

Laboratory Parameters of Bone Metabolism in Premature Infants and Children Born Using In Vitro Fertilization

Aim. To study the indicators of bone metabolism in premature babies born naturally and children born with IVF. Material and methods. The premature babies’ study was conducted, they were divided into 4 groups: depending on the method of birth and weight: 1st-children born with IVF, with very low weight; the second group – similar to the first, but children with extremely low weight; the third – children with very low weight, born naturally, with ; the fourth – similar to the 3rd, but with extremely low weight. The level of calcium, parathyroid hormone, calcitonin and C-terminal telopeptides of type I collagen was determined. Results and discussion. Diagnosis of vitamin D deficiency is possible only by measuring certain biochemical parameters, primarily the levels of its metabolites in the blood. Clinical symptoms of vitamin D deficiency in the form of rickets, osteomalacia, osteoporosis and extra-skeletal manifestations as a result of this vitamin deficiency occur over a long period of time. The most informative indicator of the body’s vitamin D supply is the content of calcidiol [25 (OH)D] in both serum and blood plasma. Vitamin D deficiency was detected in more than half (67.7±4.8%) of premature newborns in the first year of life. It seemed that in premature babies born in different ways, vitamin D deficiency was noted in 8 %, insufficiency – in 67.7 %, and the normal content in 27.5 %. In children at an early age, there is a violation of bone metabolism (an increase in the level of calcium, parathyroid hormone, calcitonin, on the one hand, and a decrease in the C-terminal telopeptides of type I collagen, on the other). These changes were associated with the weight of children, while aggressive disorders were noted in children with extremely low weight. In premature infants (with a body weight of less than 1500 g), monitoring of the level of vitamin D in the blood and C-terminal telopeptides of type 1 collagen should be recommended. Conclusion. Bone modeling has a great advantage due to the analysis of the blood serum biomarkers levels in premature infants, it enables to establish the features of osteogenesis.

Rickets in Children: An Update.

Rickets refers to a deficient mineralization of the growth plate cartilage, predominantly affecting longer bones. Despite the fact that preventive measures are available, it is still a common disease worldwide; nutritional rickets, due to vitamin D deficiency or dietary calcium inadequate intake, remains the most common form. Medical history, physical examination, radiologic features and biochemical tests are essential for diagnosis. Although recent studies suggest hypophosphatemia as the leading alteration, rickets is classically divided into two categories: calcipenic rickets and phosphopenic rickets. Knowledge of this categorization and of respective clinical and laboratory features is essential for rapid diagnosis and correct management. The aim of this review is to analyze the epidemiological, pathogenetic, clinical, and therapeutic aspects of the different forms of rickets, describing the novelties on this “long-lived” disease.

The Content Of Vitamin D Metabolites In Rachit In Children Of Early Age Who Received Specific Prevention

52 patients with rickets and 10 healthy children were examined. Among patients with rickets, 35 children were born in women with a complicated course of pregnancy (threat of termination, toxicosis of the first and second half). In 12 children, mothers had chronic liver and kidney diseases before giving birth. The level of 25(OH) vitamin D (25-oxycalciferol) and 24.25 (OH)2 vitamin D (24.25-dioxycalciferol) was determined. The content of calcium-regulating hormones in the blood serum was determined by radioimmunological analysis. To assess the severity of the rickets process, the activity of alkaline phosphatase in the blood serum was determined using a standard kit. The aim of our study was to determine the effect of specific prevention on the metabolism and course of the clinical form of rickets in young children.

X-linked Hypophosphatemic Rickets: the Challenges of Treatment

X-linked dominant hypophosphatemic rickets (XLHR) is the most common inherited form of rickets due to a mutation in the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX gene) expressed in bones and teeth. This leads to impaired renal reabsorption of phosphate and defective bone mineralization. Clinical presentation often occurs in childhood, where children mostly present with bow legs, delayed walking, or gait difficulties. Other clinical features may also be present and these are described in this review in addition to the classic laboratory findings. Focus is made on the management of XLHR and its challenges, highlighting the complications that may arise from medical treatment with reference to literature. Moreover, we also describe novel treatment in XLHR; the potential use of growth hormone and cinacalcet, and the newly approved human monoclonal antibody against FGF-23 as a more targeted therapy.

Shedding Light on Vitamin D Status and Its Complexities during Pregnancy, Infancy and Childhood: An Australian Perspective.

Ensuring that the entire Australian population is Vitamin D sufficient is challenging, given the wide range of latitudes spanned by the country, its multicultural population and highly urbanised lifestyle of the majority of its population. Specific issues related to the unique aspects of vitamin D metabolism during pregnancy and infancy further complicate how best to develop a universally safe and effective public health policy to ensure vitamin D adequacy for all. Furthermore, as Australia is considered a “sunny country”, it does not yet have a national vitamin D food supplementation policy. Rickets remains very uncommon in Australian infants and children, however it has been recognised for decades that infants of newly arrived immigrants remain particularly at risk. Yet vitamin D deficiency rickets is entirely preventable, with the caveat that when rickets occurs in the absence of preexisting risk factors and/or is poorly responsive to adequate treatment, consideration needs to be given to genetic forms of rickets.

Hypophosphatemic rickets: pathogenesis, diagnosis and treatment

Hypophosphatemic rickets (HR) - a group of diseases characterized by the development of ricketic changes in bone tissue due to increased excretion of phosphorus from the body. This form of rickets is the most common among variants of genetically determined forms of disturbances in mineral metabolism. HR is an actual medical and social problem, requiring constant updating of knowledge of both endocrinologists and doctors of other profile. This is due to the fact that the clinical picture of HR has a significant heterogeneity and can manifest as severe deformations of the skeleton, delay in physical development, severe muscle hypotension, frequent fractures, tooth abscesses, which in some cases leads to disability of the patient and, accordingly, reduces the quality of life. Timely diagnosis and adequate therapy of HR is extremely important for preventing the development of severe complications. Currently, more than 10 candidate genes are known, the defects in which lead to the development of congenital forms of GFR. Genetic diagnostics of the HR is of great importance for determining the form of the HR, and for carrying out genetic counseling of families when planning pregnancy.

Hypophosphatemic rickets: pathogenesis, diagnosis and treatment

Hypophosphatemic rickets (HR) - a group of diseases characterized by the development of ricketic changes in bone tissue due to increased excretion of phosphorus from the body. This form of rickets is the most common among variants of genetically determined forms of disturbances in mineral metabolism. HR is an actual medical and social problem, requiring constant updating of knowledge of both endocrinologists and doctors of other profile. This is due to the fact that the clinical picture of HR has a significant heterogeneity and can manifest as severe deformations of the skeleton, delay in physical development, severe muscle hypotension, frequent fractures, tooth abscesses, which in some cases leads to disability of the patient and, accordingly, reduces the quality of life. Timely diagnosis and adequate therapy of HR is extremely important for preventing the development of severe complications. Currently, more than 10 candidate genes are known, the defects in which lead to the development of congenital forms of GFR. Genetic diagnostics of the HR is of great importance for determining the form of the HR, and for carrying out genetic counseling of families when planning pregnancy.

Hypophosphatasia: Review of Bone Mineral Metabolism, Pathophysiology, Clinical Presentation, Diagnosis, and Treatment

Hypophosphatasia (HPP) is a rare, inherited form of rickets or osteomalacia due to reduced activity of tissue non-specific alkaline phosphatase (TNSALP) caused by a loss of function mutation in the TNSALP gene marked by a low serum alkaline phosphatase. The ratio of PPi to Pi is crucial in the mineralization process. This process is regulated by the interaction of three phosphatases present in matrix vesicles: the mineralization promotors TNSALP and phosphatase orphan 1 (PHOSPHO1) and the mineralization inhibitor nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1). HPP is seen worldwide affecting all races. The broad-ranging clinical severity of HPP is correlated to the pattern of inheritance and degree of TNSALP activity, with lower levels of activity seen in the more severe autosomal recessive forms. HPP is marked by compromise of phase 2 hydroxyapatite crystal formation beyond the matrix vesicle resulting in skeletal hypomineralization, spontaneous fractures, tooth loss, and chondrocalcinosis. The major forms in declining order of severity include the following: perinatal, infantile, childhood, and adult HPP in addition to OdontoHPP and benign prenatal HPP. Biochemistry typically reveals a low serum alkaline phosphatase and elevated alkaline substrates such as pyridoxal-5′-phosphate (PLP) and phosphoethanolamine (PEA). Asfotase alfa, a recent novel enzyme replacement therapy for the treatment of HPP, has transformed this once lethal disease to one that is less severe.

Rare forms of Rickets

Rare forms of Rickets

An Unusual Case of Rickets and How Whole Exome Sequencing Helped to Correct a Diagnosis

ABSTRACT Objective: Rickets can be caused by a wide variety of underlying nutritional deficiencies or genetic defects. There is significant overlap in the clinical presentations of the various forms of rickets and the risk for misdiagnosis is great. This report describes a diagnostically challenging case of rickets that highlights important differences between two forms of rickets and demonstrates how gene sequencing technology can be instrumental in the identification and further characterization of these diseases. Methods: A patient diagnosed with X-linked hypophosphatemia (XLH) as a toddler did not develop many of the classic clinical features of this disease over time, calling the diagnosis into question. Whole exome sequencing (WES) was performed in this setting to determine the genetic basis of disease. Results: WES revealed that the patient did not have any mutations associated with XLH and instead was a compound heterozygote for 2 frameshift mutations in CYP27B1, leading to a revised diagnosis of ...

Comparative study of children with calciopaenic and phosphopaenic rickets seen at Chris Hani Baragwanath Hospital

INTRODUCTION: The majority of causes of rickets can be divided into two large pathogenic groups, namely calciopaenic and phosphopaenic. Few studies have compared the clinical and biochemical presentations of the two forms of rickets. The aim of this study was to compare the demographic, clinical and biochemical presentations and response to therapy of children with calciopaenic and phosphopaenic rickets. METHODOLOGY: The study is a retrospective chart review of children diagnosed with rickets at Chris Hani Baragwanath Academic Hospital (CHBAH) in Johannesburg, South Africa, between 2006 and 2012. The radiological response to therapy was evaluated using the Thacher scoring system to assess the severity of rickets. RESULTS: The study comprises 112 patients from 2 months to 18 years of age diagnosed with rickets (53% with calciopaenic rickets and 47%with phosphopaenic rickets). The calciopaenic group was younger than the phosphopaenic group (20 [7-26] vs 36 [24-51] months; p<0.001), but the phosphopaenic group was more severely stunted than the calciopaenic group at presentation (HAZ scores -3.3 [-4.5 to -2.1] vs -2 [-3.4 to 0.7]; p<0.001. Following treatment, 75% of patients in the calciopaenic group had biomarkers that had normalised completely within a median of 13 (9-18) weeks while only 10% in the phosphopaenic group had normalised within a median of 17 (17-50) weeks. Radiological healing in response to treatment was better in the calciopaenic group compared to the phosphopaenic group (67.5% vs 18%; p-value <0.01). CONCLUSION: Calciopaenic rickets (mainly vitamin D deficiency) presented at a younger age and response to therapy was better compared to phosphopaenic rickets (mainly X-linked hypophosphataemic rickets). This study highlights the significant differences between calciopaenic and phosphopaenic rickets, which may be helpful to attending orthopaedic surgeons and paediatricians in differentiating between these two groups of rickets and in the management thereof. SUMMARY OF ABSTRACT: This study highlights the differences between calciopaenic and phosphopaenic rickets, which may be of assistance to attending orthopaedic surgeons and paediatricians in the management of rickets. The study shows that in children with calciopaenic rickets, the majority are vitamin D deficient, and present at a younger age with craniotabes and less severe lower limb deformities compared to children with phosphopaenic rickets who mainly have X-linked hypophosphataemic rickets and are severely short in stature and have genu valgum deformities. The medical management of the two types of rickets differs and response to medical therapy is better in the calciopaenic compared to the phosphopaenic group.

Teenager with Severe Bowing of Limbs

Bowing of long bones may be secondary to several aetiologies. Among the causes for bowing of long bones include congenital and acquired form of rickets, skeletal dysplasia, osteogenesis imperfecta and renal tubular acidosis (RTA).

Clinical Forms and Animal Models of Hypophosphatasia.

Hypophosphatasia (HPP) is due to mutations of the tissue non-specific alkaline phosphatase (TNAP) gene expressed in the liver, kidney, and bone. TNAP substrates include inorganic pyrophosphate cleaved into inorganic phosphate (Pi) in bone, pyridoxal-5'-phosphate (PLP), the circulating form of vitamin B6, and phosphoethanolamine (PEA). As an autosomal recessive or dominant disease, HPP results in a range of clinical forms. Its hallmarks are low alkaline phosphatase (AP) and elevated PLP and PEA levels. Perinatal HPP may cause early death with respiratory insufficiency and hypomineralization resulting in deformed limbs and sometimes near-absence of bones and skull. Infantile HPP is diagnosed before 6 months of life. Respiratory failure, rib fractures and seizures due to vitamin B6 deficiency in the brain indicate poor prognosis. Craniosynostosis is frequent. Unlike in other forms of rickets, calcium and phosphorus are not decreased, resulting in hypercalciuria and nephrocalcinosis. Hypercalcemic crisis may occur. Failure to thrive and growth retardation are concerns. In infantile and adult forms of HPP, non-traumatic fractures may be the prominent manifestation, with otherwise unexplained chronic pain. Progressive myopathy has been described. Dental manifestations with early loss of teeth are usual in HPP and in a specific form, odontohypophosphatasia. HPP has been studied in knock-out mice models which mimic its severe form. Animal models have made a major contribution to the development of an original enzyme therapy for human infantile HPP, which is however essentially targeted at mineralized tissues. Better knowledge of its extraskeletal manifestations, including pain and neurological symptoms, is therefore required.

Patulous Subarachnoid Space of the Optic Nerve Associated with X-Linked Hypophosphatemic Rickets

ABSTRACTAlthough the deficiency forms are the most common manifestations of rickets, there are other forms of rickets that are resistant to vitamin D. Of these, the most common is X-linked hypophosphatemic rickets. Rickets represents a group of multiple cranial bone disorders—craniosynostosis and the presence of Chari I malformation being the most notable—that explain the increase in intracranial pressure. We present a 4-year-old patient with an unusual association of X-linked hypophosphataemic rickets, bilateral proptosis, and prominent bilateral widening of the optic nerve sheaths. Although the association between intracranial hypertension and rickets is known, to the best of our knowledge, such a prominent distention of the subarachnoid space of the optic nerve without papilloedema has not been previously described.

Familial vitamin D resistant rickets: End-organ resistance to 1,25-dihydroxyvitamin D

Rickets is softening of bones due to defective mineralization of cartilage in the epiphyseal growth plate, leading to widening of ends of long bones, growth retardation, and skeletal deformities in children. The predominant cause is deficiency or impaired metabolism of vitamin D. The observation that some forms of rickets could not be cured by regular doses of vitamin D, led to the discovery of rare inherited abnormalities of vitamin D metabolism or vitamin D receptor. Vitamin D dependent rickets (VDDR) is of two types: Type I is due to defective renal tubular 25-hydroxyvitamin D 1-α hydroxylase and type II is due to end-organ resistance to active metabolite of vitamin D. Typical signs are observed from the first month of life. The patient with rickets described below had markedly increased serum alkaline phosphatase and 1,25-dihydroxyvitamin D. We attribute these abnormalities to impaired end-organ responsiveness to 1,25-dihydroxyvitamin D.