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A pregnancy, complicated by hypophosphatemic familial rickets (vitamin D-resistant rickets) of a female fetus, associated with atrial flutter and congestive heart failure is presented. Upon review of the literature, only 22 cases of fetal atrial flutter have been reported. The association between hypophosphatemic familial rickets and atrial flutter has not yet been described.
The effects of growth hormone therapy on the biochemical measures of bone metabolism were studied in 11 children aged 3.5 to 17 years who had familial hypophosphatemic rickets; five were male. Subjects were maintained on a regimen of stable doses of conventional therapy (calcitriol and phosphate). Subjects were studied at baseline receiving conventional therapy and during three sequential treatment periods: no therapy (4 weeks), growth hormone only (0.05 mg/kg per day for 4 weeks), and conventional therapy plus growth hormone (2 weeks). The nine youngest subjects were continued on a regimen of triple therapy for an additional 24 weeks. Serum phosphate averaged 0.93 +/- 0.13 mmol/L (mean +/- SD) at entry and decreased when the subjects were not receiving any therapy. During the 4 weeks of growth hormone only treatment, phosphate rose in all 11 subjects (0.70 +/- 0.08 mmol/L to 0.83 +/- 0.08 mmol/L). With triple therapy, phosphate remained higher than with no therapy. Calcitriol, osteocalcin, and parathyroid hormone increased as the subjects received growth hormone alone. Insulinlike growth factor I z scores rose significantly in response to growth hormone therapy alone. All nine subjects receiving 6 months of triple therapy increased their growth rate z scores. Exogenous growth hormone therapy may be useful in familial hypophosphatemic rickets.
The X-linked hypophosphatemic rickets is a rare metabolic disorder characterized by low serum phosphate levels caused by a decreased renal tubular reabsorption of inorganic phosphates. The initial complaints are a delay in the development of walking caused by deformity of the legs. Oral findings include poorly mineralized dentin, enlarged pulp chambers and root canals, and periradicular abscesses in caries-free teeth. We present three patients from the same family with X-linked hypophosphatemic rickets showing bone and dental alterations.
A method for assay of 25-hydroxyvitamin D-24-hydroxylase (24-hydroxylase) activity in phytohemagglutinin (PHA)-stimulated lymphocytes was applied to determine whether vitamin D-dependent rickets type II (VDDR II) is hereditary. In normal lymphocytes incubated with PHA for 3 days, maximal and half-maximal responses of 24-hydroxylase were observed after exposure to 10(-8) mol/L and (1.3 +/- 0.4) x 10(-9) mol/L 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], respectively. These responses were similar to those of cultured skin fibroblasts. In contrast, after exposure to 10(-8), 10(-7), and 10(-6) mol/L 1,25-(OH)2D3, no 24-hydroxylase activity was detected in cells from patients with VDDR II, and intermediate activity was observed in cells from their parents. These findings indicated the presence of an intracellular receptor-effector system for 1,25-(OH)2D3 in peripheral lymphocytes. Heterozygotes of VDDR II could be identified, and autosomal recessive inheritance of the disease was demonstrated. Detection of heterozygotes of this disease was not possible by assay of inhibition of thymidine incorporation, another marker of the function of 1,25-(OH)2D3 in PHA-stimulated lymphocytes. Therefore, assay of 24-hydroxylase induction reflected the receptor status more closely than assay of inhibition of DNA biosynthesis. The assay of 24-hydroxylase activity in PHA-stimulated lymphocytes described here will be useful for diagnosis of VDDR II and study of families of patients with this disease.
A patient is described who has Morquio syndrome (MPS IVA). He is a member of the Hutterite Brethren and genealogic analysis discloses a high inbreeding coefficient for the proband. The proband's sibship is segregating two autosomal recessive disorders, ie, MPS IVA and infantile hypophosphatasia. Two other families each have one or the other of these diseases but not both. The three families are distantly related.
A recent therapeutic development consists in the utilization of vitamins as pharmacological agents in the treatment of a variety of diseases. The growth defect accompanying deficiency rickets and other forms of refractory rickets can be prevented or corrected, at least partially, by the use of high doses of its metabolites, 25 OH D3, 1,25 (OH)2 D3, 1 OH D3. On the basis of many published studies and of a few patients personally observed it is possible to delineate the form and the dosage of these drugs for the treatment of vitamin D dependent rickets and of the bone lesions in renal insufficiency, in familial hypophosphatemic rickets and in complex tubulopaties. In some of these a dietetic treatment in association with vitamin D or its metabolites may be essential.
Proper serum phosphate concentrations are maintained by a complex and poorly understood process. Identification of genes responsible for inherited disorders involving disturbances in phosphate homeostasis may provide insight into the pathways that regulate phosphate balance. Several hereditary disorders of isolated phosphate wasting have been described, including X-linked hypophosphataemic rickets (XLH), hypophosphataemic bone disease (HBD), hereditary hypophosphataemic rickets with hypercalciuria (HHRH) and autosomal dominant hypophosphataemic rickets (ADHR). Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH (refs 6,7). ADHR (MIM 193100) is characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses. Here we describe a positional cloning approach used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence. We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23. These mutations in patients with ADHR represent the first mutations found in a human FGF gene.
A 2 1/2 year old girl in whom familial hypophosphataemic rickets was diagnosed at age 2 months, has been treated since then with oral 1 alpha,25-dihydroxycholecalciferol and phosphate. She has not, so far, developed osseous lesions.
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).
In a case of familial hypophosphatemic rickets, marked bone thickening caused narrowing of the optic canals, resulting in bilateral optic atrophy. The case also showed metastatic calcification in the walls of both globes.
This paper presents three markers, 16D/E, pHMAI (DXS208), and CRI-L1391 (DXS274), that show close linkage for X-linked hypophosphataemic rickets (HYP). DXS274 is closely linked to HYP (theta max = 0.00, Zmax = 4.20), and DXS41 (99.6), (theta max = 0.00, Zmax = 5.20). Marker 16D/E maps distal to the disease locus (theta max = 0.05, Zmax = 3.11). The pHMAI probe recognises the same restriction fragment length polymorphism (RFLP) as 99.6. Multipoint analysis suggests that the most probable order of loci is Xpter-(DXS43, 16D/E)-HYP-DXS274-(DXS208, DXS41)-Xcen. The location of DXS274 distal to HYP cannot be excluded, as no recombinants were observed between DXS274 and HYP, or between DXS274 and DXS41/DXS208. One of the families contains a large number of recombinants, four of which are double recombinants. This most probably means that the disease in this family maps elsewhere on the X chromosome or on an autosome, indicating locus heterogeneity.
X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterised by impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules. By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes, members of which are involved in the degradation or activation of a variety of peptide hormones. This gene (which we have called PEX) is composed of multiple exons which span at least five cosmids. Intragenic non-overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients, which suggest that the PEX gene is involved in the HYP disorder.
Fibroblasts from three patients with vitamin D-dependency rickets type II were used to study mutations in the 1,25-dihydroxyvitamin D3 receptor responsible for this hereditary disease. Normal human fibroblasts contain 43 +/- 13 fmol receptor/mg protein as determined by immunoradiometric assay and 22 +/- 3 fmol/mg by ligand binding assay. The fibroblasts from the rachitic patients contained no receptor detectable by either method. The 1,25-(OH)2D receptor cDNA for cells from each kindred was produced from total RNA using reverse transcription and polymerase chain reaction amplification. When these cDNAs were sequenced, it was found that each cell line contained a nucleotide substitution resulting in a stop codon in the coding sequence. The predicted resultant receptor protein is 69 amino acids long in one family, and 148 and 291 amino acids long in two other families. These truncated proteins have little or no 1,25-dihydroxyvitamin D3-binding domain accounting for 1,25-dihydroxyvitamin D resistance.
In 20 children with tibial and femoral bones deformities due to hypophosphatemic rickets a corrective osteotomy/osteoclasis at 2 or 4 sites was performed. Both preoperative and postoperative pharmacological treatment was introduced. Good results were achieved in 13 cases, satisfactory an 4 and bad in 3 cases.
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.
Structural deformities of deciduous teeth from patients with hypophosphatemic vitamin D-resistant rickets (HVDRR) (1 male and 2 female patients) were examined by means of transmitted light microscopy, contact microradiography, and x-ray microanalysis. Freshly extracted teeth were fixed in formalin and subsequently hemisected longitudinally through the midline. One half was prepared for ground sections and the other half for decalcified sections. Neither gross nor microscopic abnormalities were present in enamel of patients with HVDRR. The concentration of calcium and phosphorus and the calcium/phosphorus ratio of the enamel of patients with HVDRR were nearly equal to those of normal teeth, although the degree of radiopacity was less in HVDRR. On the other hand, numerous microscopic abnormalities in the dentin of patients with HVDRR were found, such as interglobular dentin, wide predentin zones, and tubular defects. The concentration of phosphorus in the dentin of a patient with familial HVDRR was extremely low. Furthermore, formation of reparative dentin was observed at the pulp horn of teeth in patients with HVDRR that had been subjected to definite attrition at the corresponding dentin site.
X-linked hypophosphatemic rickets and autosomal dominant hypophosphatemic rickets are inherited phosphate wasting disorders. X-linked hypophosphatemic rickets results from mutations in the PHEX gene, which codes for a protein that is a member of the neutral endopeptidase family. The gene that is responsible for autosomal dominant hypophosphatemic rickets has not yet been identified, however, positional cloning studies have narrowed the gene locus to chromosome 12p13. This review will focus on the pathogenesis of these disorders and how these disorders provide insight into normal phosphate homeostasis.
BACKGROUND: At present the genetic defect for autosomal recessive and autosomal dominant hypophosphataemic rickets with hypercalciuria (HHRH) is unknown. Type II sodium/phosphate cotransporter (NPT2) gene is a serious candidate for being the causative gene in either or both autosomal recessive and autosomal dominant HHRH. In the present study we tested this hypothesis in one autosomal recessive family. METHODS: The gene structure of human NPT2 is known. We tested the complete open reading frame in the affected siblings by polymerase chain reaction in combination with automatic DNA sequencing for the presence of mutations. RESULTS: We did not observe disease-causing mutations in the NPT2 gene of the affected siblings. A T855C polymorphism resulting in a histidine to arginine transition was present in the open reading frame of NPT2. The polymorphism was present in both affected as well as unaffected family members. CONCLUSION: The hypothesis that a defect in the NPT2 gene could be an underlying cause for autosomal recessive HHRH could not be sustained in our study.