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PubMed1996

Minnesota rickets. Need for a policy change to support vitamin D supplementation.

Vitamin D deficiency rickets, once considered the most common disease of early childhood, was reported to have disappeared by the 1960s. However, during a recent 18-month period, seven cases of nutritional rickets were diagnosed in the Twin Cities metropolitan area. All of the patients were born at term and were breastfed without supplementation vitamins. Three of the patients were Caucasian, three were African American, and one was biracial. This case series demonstrates the risk of nutritional rickets in breastfed infants in our northern climate, regardless of race. In hopes of eradicating this completely preventable disease, we advocate a uniform policy of vitamin D supplementation to breastfed infants.

Breast Feeding↗

PubMed1988

Familial glucocorticoid deficiency in a girl with familial hypophosphatemic rickets.

Familial glucocorticoid deficiency is a rare multisystem disorder characterized by glucocorticoid deficiency with normal mineralocorticoid activity, achalasia of the cardia, and alacrima. Familial hypophosphatemic rickets is characterized by selective renal phosphate wasting with subsequent hypophosphatemia and an inappropriately low 1,25-dihydroxyvitamin D concentration for the degree of hypophosphatemia. A 6-year-old girl with both disorders is described. A biochemical relationship between familial glucocorticoid deficiency and familial hypophosphatemic rickets could not be defined; the influence of cortisol on her serum calcium level, phosphorus level, and rickets, as well as the natural history of these two entities, is described.

Child↗

PubMed1991

Vitamin D dependent rickets type II with myelofibrosis and immune dysfunction.

We present a new patient with vitamin D dependent rickets type II. A 20-month-old Arabian boy whose parents are first cousins showed florid rickets, myelofibrosis and recurrent septicaemia. In addition to absent specific binding for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). 25-Hydroxyvitamin D3-24-hydroxylase activity could not be induced in cultured fibroblasts. The patient did not respond to 99 micrograms 1,25(OH)2D3 per day, but skeletal and haematological abnormalities improved with daily infusion of 100 mg/kg calcium, as serum parathyroid hormone levels fell to normal values. At the age of 7 years, he died from pneumonia. The improvement of haematological abnormalities with calcium infusions but not with 1.25(OH)2D3 suggests a pathogenetic relationship of myelofibrosis and hyperparathyroidism. Having anti-lipid A IgM antibody titres up to 1:10.000 after Gram negative septicaemias, the patient never produced corresponding IgG antibodies. His neutrophil chemotaxis was persistently reduced to 57% +/- 3% of age-matched controls (P less than 0.028). The patient showed two pathological immune functions considered to contribute to the well-known susceptibility to infection in rickets.

Calcium↗

PubMed2000

Morphological and functional features of clasts in low phosphate, vitamin D-deficiency rickets.

Focusing on resorption processes, we have extended our previous studies on chondroclasts and osteoclasts in normally developing tissues, using a model of nutritionally induced vitamin D-deficiency rickets. To analyze the resorption process, we investigated the matrix-resorbing cells in this modified and poorly mineralized tissue regarding morphological features and expression of tartrate-resistant acid phosphatase (TRAP) at the subcellular level. Our goal was to test the hypotheses that initiation of resorption is impaired with unmineralized matrix, and that such alterations involve changes in the subcellullar distribution of TRAP, implicating a role for this enzyme in the resorption process. Our results reveal distinctly different morphological appearances of clast-like cells in rickets compared with normal osteoclasts and chondroclasts. Ordinary resorption structures of osteoclasts and chondroclasts at the cell-matrix border, i.e., ruffled borders and clear zones, are profoundly altered in favor of a less well-defined intermediate zone. TRAP distribution at the subcellullar level is also clearly different from that in osteoclasts and chondroclasts from normal rodents, with impaired secretion; consequently, the enzyme is unable to function in the matrix outside the ruffled border. Our ultrastructural observations demonstrate that in rickets, the clasts are incapable of degrading the poorly mineralized cartilage and bone efficiently. Rachitic clasts seem to be recruited to the matrix surface and interaction between cell and matrix is also initiated, but definitive resorption structures at the cell-matrix border are not normally developed. Whether resorption is inhibited by the mere lack of mineral or mineral-associated proteins, or by other mechanisms remains to be settled.

Acid Phosphatase↗

PubMed2006

Growth in X-linked hypophosphatemic rickets.

Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR--20 girls, seven boys--diagnosed at a median (md) of 1.46 years of age, (range 0.39-8.5 years), were studied at 10.12 years of age (1.58-18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was -1; (-4.58; 0.54) md (range). After 5 years' follow-up (0.92-15.6), Z-height was -0.91 (- 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a "catch up" phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height </= -2SD at the last visit, and impaired linear growth was associated with age >2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.

Adolescent↗

PubMed2004

Resolution of severe, adolescent-onset hypophosphatemic rickets following resection of an FGF-23-producing tumour of the distal ulna.

Oncogenic hypophosphatemic osteomalacia (OHO) is an uncommon hypophosphatemic syndrome characterized by bone pain, proximal muscle weakness and rickets. It has been postulated that OHO results from overproduction of a humoral phosphaturic factor by an occult tumour. Recently, some OHO tumours have been shown to elaborate fibroblast growth factor-23 (FGF-23), which causes renal phosphate wasting when administered to mice. The purpose of this study was to undertake detailed investigations to confirm the diagnosis of OHO in a pediatric patient and to document the biochemical, radiographic and bone histological phenotype before and after tumour removal. We describe an 11-year-old, previously healthy girl with significant pain and functional disability associated with hypophosphatemic rickets. Circulating 1,25-(OH)(2) vitamin D was very low (14 pM; N: 40-140) while the FGF-23 serum level was markedly elevated [359.5 reference units (RU)/ml, N: 33-105]. An iliac bone biopsy revealed severe osteomalacia, but periosteocytic lesions, as are typical for X-linked hypophosphatemic rickets, were not seen. Sequence analyses of the PHEX and FGF23 genes were normal. A radiographic skeletal survey revealed a small exostosis of the left, distal ulnar metaphysis. A tumour was subsequently removed from this site and the pathology was consistent with benign, fibro-osseous tissue. Serum FGF-23 was normal when measured at 7 h post-operatively, while serum phosphate reached the low-normal range at 16 days following surgery. An iliac bone biopsy taken 5 months after the operation showed improvement, but not yet resolution, of the osteomalacia. Biochemical parameters of bone and mineral metabolism suggested that complete resolution of the osteomalacia was not achieved until 12 months following surgery. One year after tumour removal, the patient was pain-free and had resumed a normal level of activity. The rapid normalization of FGF-23 levels following removal of a benign tumour and the subsequent improvement in the biochemical and histological parameters of bone and mineral metabolism suggest that FGF-23 played a key role in this girl's disease.

Base Sequence↗

PubMed1989

Vitamin D-deficiency rickets and myelofibrosis.

This study was aimed at detecting the early appearance of myelofibrosis by bone marrow biopsy examination in children with vitamin D-deficiency rickets. Twelve children, aged 4 to 18 months, were evaluated. Only a minimal increase of the reticulin was shown in rachitic children without anemia in whom no other laboratory evidence of myelofibrosis was present. Early signs of myelofibrosis with increase of reticulin were present in rachitic infants with anemia. In patients of the same age with iron deficiency anemia, the bone marrow reticulin findings were normal. Bone marrow biopsy after successful treatment of rickets could be repeated in one patient with myelofibrosis; results indicated that the myelofibrosis with anemia associated with vitamin D-deficiency rickets is reversible by vitamin D treatment.

Anemia, Hypochromic↗

PubMed1996

Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets.

OBJECTIVE: Conventional treatment of familial hypophosphaiaemic rickets with oral phosphate and 1 alpha-hydroxycholecalciferol (1 alpha HCC) does not satisfactorily correct the metabolic or physical defects of the disease and can have adverse effects, such as nephrocalcinosis. Hyperoxaluria from increased oral phosphate intake may contribute to nephrocalcinosis. Growth hormone enhances renal tubular phosphate reabsorption and 1,25-dihydroxy-cholecalciferol production in normal and in GH deficient individuals, and may thus be of benefit to patients with familial hypophosphataemic rickets. PATIENTS: We have assessed the acute effects of GH on phosphate and calcium metabolism in 6 children (age 4-14 years) with familial hypophosphataemic rickets. DESIGN: Each patient served as his/her own control and received the following in a sequential non-randomized design: conventional treatment with oral phosphate 1.0-3.4 mmol/kg/day in 3-6 divided doses and 1 alpha HCC 18-31 ng/kg/day-no treatment-GH 0.05 mg/kg daily-GH and 1 alpha HCC-and GH with phosphate and 1 alpha HCC. Each treatment was given for 7 days with 7 day periods of no treatment in between. MEASUREMENTS AND RESULTS: Glomerular filtration rate, tubular maximum rate of phosphate reabsorption per litre of glomerular filtrate (TmP/GFR) and serum 1,25-dihydroxycholecalciferol increased with GH. Mean 24-hour plasma phosphate concentrations did not increase with GH but were higher in the treatment phases which included phosphate and 1 alpha HCC (P = 0.002). Serum PTH was higher when GH was given in combination with phosphate and 1 alpha HCC compared to other phases. Urine oxalate excretion did not differ between the treatment phases. CONCLUSIONS: GH seemed to partially correct the defects in renal tubular phosphate transport and 1 alpha-hydroxylation of 25-hydroxycholecalciferol. We speculate that the net effect of GH treatment was an increase in body phosphate, although this was not reflected in a change in plasma phosphate. Therefore, GH in combination with 1 alpha HCC may act as a phosphate sparing agent, permitting treatment with lower and less frequent doses of oral phosphate and reducing adverse effects such as nephrocalcinosis.

Adolescent↗

PubMed2003

Vitamin D-dependent rickets Type II with alopecia: two case reports and review of the literature.

Vitamin D-dependent rickets Type II is a rare autosomal recessive disorder. It usually presents with rachitic changes not responsive to Vitamin D treatment with elevated circulating levels of 1,25-Dihydroxyvitamin D3, thus differentiating it from Vitamin D-dependent rickets Type I. Alopecia of the scalp or the body is seen in some families with Vitamin D-dependent rickets Type II. This is usually associated with more severe resistance to Vitamin D. We report two Saudi brothers with this disease, and review the salient features of this disease with emphasis on the associated alopecia.

Alopecia↗

PubMed1998

CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets.

This study demonstrates that a missense mutation in the voltage gated chloride channel, CLCN5, can cause X-linked renal failure without X-linked recessive hypophosphatemic rickets. A large kindred (Family A), initially evaluated in 1974 with an inherited syndrome characterized by hypercalciuria, nephrocalcinosis, low molecular weight proteinuria, renal tubular acidosis, and renal failure, was clinically re-evaluated and genetically characterized. Medical histories, physical examinations, blood chemistries, and 24-hour urine collections were obtained from 48 family members. Both female and male family members exhibited hypercalciuria, nephrolithiasis, and low molecular weight proteinuria. However, only men developed renal insufficiency, consistent with an X-linked recessive gene defect. Genetic linkage located the disease locus on the proximal short arm of the X chromosome (Xp11) where a voltage gated chloride channel gene, CLCN5, had previously been mapped. DNA sequence of the CLCN5 gene demonstrated a missense mutation (Ser244Leu) in affected family members. The same missense mutation has previously been shown to cause X-linked recessive hypophosphatemic rickets. No affected member of Family A had evidence of chronic hypophosphatemia, clinically significant rickets, or osteomalacia. We hypothesize that genetic background, environment, diet, or an unidentified modifying gene may account for the differing phenotypes resulting from this shared gene defect.

Adolescent↗

PubMedDate not supplied

[Early diagnosis and early treatment of hypophosphatemic vitamin D-resistant rickets].

This is a report on two children with hypophosphatemic vitamin D-resistant rickets born to affected mothers diagnosed at the age of one and three months, respectively. The most important diagnostic criterium is the reduced value of the transport maximum of phosphorus in relation to glomerular filtration rate. At the age of one and six months, respectively, therapy with 1.25 (OH)2D3 and phosphate was started with the result of normal growth of length, radiological healing of rickets and normalisation of alkaline serum-phosphatase, but persistently low fasting values of serum-phosphorus during the time of observation up to twelve and twenty-four months of age, respectively in both children. The therapy with 1.25 (OH)2D3 and phosphate has a positive effect on intestinal absorption of phosphorus, because the serum-phosphorus is significantly elevated to the age corrected normal range two hours after oral administration of phosphate. There were no negative effects during therapy. It seems, therefore, that early diagnosis and therapy with 1.25 (OH)2D3 and phosphate is successful in healing this rare form of rickets.

Calcitriol↗

PubMed1991

Effects of therapy in X-linked hypophosphatemic rickets.

BACKGROUND: Patients with X-linked hypophosphatemic rickets, which is clinically manifested by growth failure and bowing of the legs, are usually treated with phosphate and a vitamin D preparation. However, the efficacy of this treatment has been disputed, and nephrocalcinosis is a recognized complication of therapy. METHODS: We studied 24 patients with X-linked hypophosphatemic rickets (9 boys and 15 girls) ranging in age from 1 to 16 years (median, 5.3). The duration of combination therapy ranged from 0.3 to 11.8 years (median, 3.0). We measured height as a standard-deviation (SD) score (the number of SDs from the mean height for chronologic age). Measurements made before the age of two years or after the onset of puberty were excluded. We compared the results with those reported in 1971 for 16 untreated prepubertal Australian patients. We also determined the severity of nephrocalcinosis (on a scale of 0 to 4, with 0 indicating no abnormalities and 4 stone formation) with renal ultrasonography and whether it could be related to the dosage of phosphate or vitamin D or to other factors. RESULTS: Patients treated for at least two years before the onset of puberty (n = 19) had a mean height SD score of -1.08, as compared with -2.05 in the untreated historical controls. The 13 patients who had been treated with calcitriol and phosphate for at least two years had an increase in the mean height SD score of 0.33, from -1.58 to -1.25 (95 percent confidence interval, 0 to 0.67; P = 0.05). Nineteen of the 24 patients (79 percent) had nephrocalcinosis detected on renal ultrasonography. The grade of nephrocalcinosis was significantly correlated with the mean phosphate dose (r = 0.60, P = 0.002), but not with the dose of vitamin D or the duration of therapy. All patients had normal serum creatinine concentrations. CONCLUSIONS: Therapy with calcitriol and phosphate may increase the growth of children with X-linked hypophosphatemic rickets. Nephrocalcinosis in these children represents a complication of therapy and is associated with the dose of phosphate received.

Body Height↗

PubMed1989

An ochre mutation in the vitamin D receptor gene causes hereditary 1,25-dihydroxyvitamin D3-resistant rickets in three families.

Hereditary 1,25-dihydroxyvitamin D3-resistant rickets is a rare autosomal-recessive disease resulting from target-organ resistance to the action of the active hormonal form of vitamin D. Four affected children from three related families with the classical syndrome of hereditary 1,25-dihydroxyvitamin D3-resistant rickets and the absence of detectable binding to the vitamin D receptor (VDR) in cultured fibroblasts or lymphoblasts were examined for genetic abnormalities in the VDR gene. Genomic DNA from Epstein-Barr virus-transformed lymphoblasts of eight family members was isolated and amplified by polymerase chain reaction techniques. Amplified fragments containing the eight structural exons encoding the VDR protein were sequenced. The DNA from all affected children exhibited a single C----A base substitution within exon 7 at nucleotide 970 that resulted in the conversion of the normal codon for tyrosine (TAC) into a premature termination codon (TAA) at amino acid 292. This mutation causes a truncation of the VDR protein thereby deleting a large portion of the steroid hormone binding domain (amino acids 292-424). Although the affected children were all homozygotic for the mutation, the four parents tested all exhibited both wild-type and mutant alleles, indicating a heterozygous state. The functional consequences of this mutation were confirmed after expression of the recreated mutant VDR cDNA in mammalian cells. Recreated mutant receptor exhibited no specific 1,25-[3H]dihydroxyvitamin D3 binding and failed to activate a cotransfected VDR promoter-reporter gene construct. Thus these findings identify an ochre mutation in a human steroid hormone receptor in patients with hereditary 1,25-dihydroxyvitamin D3-resistant rickets.

Amino Acid Sequence↗

PubMed2006

Deformity correction by external fixation and/or intramedullary nailing in hypophosphatemic rickets.

BACKGROUND: There are many modalities of treatment for complex lower extremity deformity in hypophosphatemic rickets. We evaluated the outcomes of deformity correction using an external fixation and/or intramedullary nailing in hypophosphatemic rickets. PATIENTS AND METHODS: 55 segmental deformities (20 femora, 35 tibiae) from 20 patients were examined retrospectively. There were 9 children and 11 adults. Distraction osteogenesis was used in 28 segments and acute deformity correction in 27. External fixation was applied in 24 segments, intramedullary nailing in 6, and external fixation and intramedullary nailing in 25. RESULTS: There were 18 major and 13 minor complications in 26 of 28 segments with distraction osteogenesis, and 13 major and 10 minor complications in 19 of 27 segments with acute correction. Recurrent deformity or refracture occurred in 10 of 21 segments with distraction osteogenesis by external fixation only, 4 of 6 with acute correction by intramedullary nailing, and 1 of 25 with distraction osteogenesis or acute correction by external fixation and intramedullary nailing. Nail-related complications occurred in 3 of 6 with intramedullary nailing and 2 of 25 with external fixation and intramedullary nailing. INTERPRETATION: External fixation and intramedullary nailing can be recommended to prevent complications during or after deformity correction in hypophosphatemic rickets.

Adolescent↗

PubMed2002

Cervical spinal cord compression attributable to a calcified intervertebral disc in a patient with X-linked hypophosphatemic rickets: case report and review of the literature.

OBJECTIVE AND IMPORTANCE: X-linked hypophosphatemic rickets is a common inherited phosphate-wasting disorder, but it is a rare cause of spinal cord compression. We present the first reported case of a calcified intervertebral disc causing spinal canal stenosis in X-linked hypophosphatemic rickets. CLINICAL PRESENTATION: A 44-year-old woman presented with paresthesia of her left arm and a loss of grip in both hands. Magnetic resonance imaging revealed a calcified intervertebral disc, as well as a posterior osteophytic bar causing marked cervical cord compression at C6/C7. INTERVENTION: An anterior cervical discectomy at C6/C7 and fusion with autologous bone graft were performed. The patient then exhibited significant improvement. CONCLUSION: A review of the 16 published cases demonstrates that thickening of the vertebral laminae, facet joint hypertrophy, and ossification of the intervertebral discs, posterior longitudinal ligament, and/or ligamentum flavum contribute to spinal canal stenosis in X-linked hypophosphatemic rickets. Those changes are caused by the disease itself and are unlikely to be related to long-term vitamin D treatment. Eleven of 16 patients were reported to have experienced favorable outcomes after surgery.

Adult↗

PubMed1987

Bridging markers defining the map position of X linked hypophosphataemic rickets.

Hypophosphataemic rickets is commonly an X linked dominant hereditary disorder associated with a renal tubular defect in phosphate transport and bone deformities. The gene causing this disorder has been mapped to Xp22.31----p21.3 by using cloned human X chromosome sequences identifying restriction fragment length polymorphisms (RFLPs) in linkage studies of affected families. The hypophosphataemic rickets gene locus (HPDR) was previously mapped distal to the X linked polymorphic locus DXS41 (99.6) but its position in relation to the distal loci DXS43 (D2) and DXS85 (782) was not established. In order to obtain a precise mapping of the disease locus in relation to these genetic loci, additional affected families informative for these X linked markers have been investigated. The combined results from the two studies have established linkage with the loci DXS41 (99.6) and DXS43 (D2); peak lod score for DXS41 (99.6) = 7.35, theta = 0.09, and peak lod score for DXS43 (D2) = 4.77, theta = 0.16. Multilocus linkage analysis mapped the hypophosphataemic rickets gene distal to the DXS41 (99.6) locus and proximal to the DXS43 (D2) locus, thereby revealing two bridging genetic markers for the disease.

Chromosome Mapping↗

PubMed1999

Hereditary hypophosphataemic rickets: report of a family from the Indian subcontinent.

Nutritional deficiency continues to be an important cause of rickets in the underdeveloped and developing parts of the world. In the western hemisphere, predominantly non-nutritional forms of rickets and osteomalacia are now seen. In this report we discuss a family with X-linked hypophosphataemic rickets from the Kashmir region of the Indian subcontinent (which is an uncommon entity here).

Adolescent↗

PubMed2003

Schimmelpenning-Feuerstein-Mims syndrome with hypophosphatemic rickets.

The Schimmelpenning-Feuerstein-Mims syndrome (SFM syndrome) is a rare and variable multisystem defect consisting of congenital, extensive linear nevus sebaceus and associated abnormalities in different neuroectodermal organ systems. We present the history of a 52-year-old female patient with disproportionate hyposomia and asymmetric constitution. From birth she suffered from a right-sided, extensive nevus sebaceus following Blaschko's lines extending on the scalp, neck, right arm and trunk. At the age of 5 years, she developed a generalized growth retardation, along with deformations of bones. At the age of 11, hypophosphatemic rickets was diagnosed causing this growth retardation. Moreover, the patient developed a precocious puberty at the age of 9 years. When we saw the patient 40 years after the diagnosis had been made, phosphaturia had returned to normal. Specific therapy of hypophosphatemic rickets is straightforward and efficient in preventing late complications like growth retardation. We suggest to conduct appropriate laboratory tests in early childhood in patients with an extensive systematized sebaceous nevus or with additional signs of growth retardation or skeletal involvement, in order to exclude hypophosphatemic rickets associated with SFM syndrome.

Abnormalities, Multiple↗