Hepatitis C-associated osteosclerosis after blood transfusion.
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Adult↗
Biomedical subjects
M P Whyte
Publications and source records attributed to M P Whyte.
X-linked hypophosphatemia: normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2-induced renal azotemia.
Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.
Adult↗
Searching for gene defects that cause high bone mass.
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Bone Density↗
Paget bone disease involving young adults in 3 generations of a Korean family.
Although the etiology of Paget bone disease (PBD) is unknown, increasing evidence implicates a "slow virus" infection of the skeleton, perhaps in genetically predisposed individuals. PBD is rare in Asia. We describe a Korean family with PBD. The propositus noticed bowed limbs at approximately 25 years of age. Radiologic studies made when he was 55 years old revealed essentially panostotic PBD. Serum alkaline phosphatase (ALP) activity and osteocalcin (OC) levels were markedly elevated. An iliac crest specimen showed classic histopathologic changes of PBD. Additionally, palpable swellings were first observed at age 45 years at his occiput, pubic ramus, ileum, and facial bones. They contained numerous multinucleated cells and were originally diagnosed as giant cell tumors. However, we found that, like osteoclasts, these cells expressed considerable tartrate-resistant acid phosphatase activity. These "extraskeletal osteoclastomas" resolved rapidly with dexamethasone treatment. Two daughters, 20- and 24-years-of-age, were discovered by study of his 5 children to have elevated serum ALP activity and OC levels and widespread PBD. Both women, however, are without palpable masses and are asymptomatic. The propositus' father, who died at age 55 years, had similar skeletal deformities beginning at age 20 years, but was not examined. Leukocytopenia was found in the 3 living family members with PBD. There was no evidence for linkage of the PBD to HLA loci. The condition appears to be transmitted as an autosomal dominant trait and is manifest in young adult life. Multicentric extraskeletal osteoclastomas with remarkable sensitivity to dexamethasone treatment appear to be another unusual feature of this family's disorder. In this family, the stimulus for PBD is so great that the PBD is apparent at an early age, affects essentially the entire skeleton, and leads to the formation or extension of osteoclast-like cells into nonosseous tissues (extraskeletal osteoclastomas). This 3-generation kindred in Korea, where PBD is rare, shows a strong clustering of PBD compatible with autosomal dominant inheritance. Leukocytopenia appears to distinguish affected family members, but any role for this abnormality in the pathogenesis of PBD is unclear. Our findings support a heritable diathesis for PBD, perhaps mediated by an immune deficiency.
Adult↗
Calcinosis universalis complicating juvenile dermatomyositis: resolution during probenecid therapy.
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Adult↗
Extraskeletal osteoclastomas responsive to dexamethasone treatment in Paget bone disease.
Giant cell tumors (GCTs) of bone, also called osteoclastomas, complicate Paget bone disease (PBD), though infrequently. Giant cell reparative granulomas (GCRGs), which are histologically similar to GCTs, also occur rarely in pagetic patients. A 45-yr-old black woman with neurofibromatosis, type I, and polyostotic PBD developed slowly-growing masses in the right posterior iliac and left upper parasacral regions. She had multiple cutaneous neurofibromas and café-au-lait spots. Serum alkaline phosphatase activity and urine hydroxyproline levels were elevated. Skeletal radiographs and bone scintigraphy showed changes of widespread PBD. Computerized tomography and magnetic resonance imaging (MRI) delineated masses in the right gluteal and the left lower lumbar paraspinal regions. Five additional smaller masses were found in the abdomen and in the pelvis. Biopsy of the right gluteal mass revealed a GCT. However, we found that this lesion had several histologic features distinct from those of giant cell reparative granulomas or GCT. In our patient's tumor, the huge polykaryons, like osteoclasts, expressed abundant tartrate-resistant acid phosphatase activity, whereas those of GCRG lack this enzyme. Although the polykaryons in conventional GCTs and GCTs in PBD express tartrate-resistant acid phosphatase activity, the location of these tumors in bone differs from the extraskeletal masses encountered in our patient. Furthermore, the larger size of the polykaryons and the greater number of nuclei in our patient's GCT differ from conventional GCTs, but not GCTs in PBD. Her extraskeletal osteoclastoma rapidly shrunk to one third its original size during 2 weeks of oral dexamethasone treatment. Significant clinical improvement lasted about 5 months before additional courses of dexamethasone therapy were necessary. Injections of synthetic salmon calcitonin alone did not affect the tumor's size. Thus, PBD can be complicated by extraskeletal tumors that seem to contain osteoclasts and are responsive to dexamethasone treatment.
Bone Neoplasms↗
Linkage studies of a Missouri kindred with autosomal dominant spondyloepimetaphyseal dysplasia (SEMD) indicate genetic heterogeneity.
A four-generation kindred (14 affected and 10 unaffected members) from Missouri, U.S.A. in which spondyloepimetaphyseal dysplasia (SEMD) had been inherited as an autosomal dominant disorder was investigated for linkage to 13 candidate loci: COL2AI, COL9AI, COL9A2, COL9A3, COL10A1, COL11A1, COL11A2, PSACH, FGFR3, decorin, CRTL1, COMP, and PTHRP. Mutations of COL2A1, COL9A2, COL10, and FGFR3 have been reported previously in the Strudwick type of SEMD, multiple epiphyseal dysplasia type 2 (EDM2), the Schmid type of metaphyseal dysplasia, and in achondroplasia, respectively, and the pseudoachondroplasia (PSACH) locus has been mapped to chromosome 19p12. In addition, mutations in COL9 and COL11A are associated with murine forms of degenerative joint disease and chondroplasia, respectively. The family proved informative for 12 of the 13 loci and was uninformative at the decorin locus. Linkage between this form of SEMD, designated the Missouri variant, SEMDMO, and the 12 informative candidate loci was excluded (LOD scores < -2.00 at theta = 0.005 to 0.15), thereby indicating further genetic heterogeneity in these inherited disorders of bone and cartilage development.
Chromosome Aberrations↗
mtDNA analysis shows common ancestry in two kindreds with X-linked recessive hypoparathyroidism and reveals a heteroplasmic silent mutation.
Two kindreds residing in eastern Missouri and exhibiting X-linked recessive idiopathic hypoparathyroidism have been described. Genealogical records extending back five generations revealed no common ancestor. To investigate the possibility of relatedness, the DNA sequence of the mitochondrial D-loop was compared among several individuals in both kindreds. The mtDNA D-loop was amplified from the total DNA of individuals by use of nested PCR reactions, and the resulting 430-bp fragment was sequenced. The mtDNA sequence was identical among affected males and their maternal lineage for individuals in both kindreds. Conversely, the mtDNA sequence of the fathers of the affected males differed from that of the maternal lineage at three to six positions. These results demonstrate that the two kindreds exhibiting X-linked recessive hypoparathyroidism are indeed related and that an identical gene defect is responsible for the disease. A further feature of the inheritance pattern was examined when a unique point mutation was identified in the mtDNA of one branch of one of the kindreds. This mutation appears to be de novo and segregates in subsequent generations without obscuring relatedness. In addition, the results of our study of mtDNA analysis indicate that this approach may be of importance in investigating common ancestry in other X-linked disorders.
Alleles↗
Matrix vesicles in osteomalacic hypophosphatasia bone contain apatite-like mineral crystals.
Hypophosphatasia, a heritable disease characterized by deficient activity of the tissue nonspecific isoenzyme of alkaline phosphatase (TNSALP), results in rickets and osteomalacia. Although identification of TNSALP gene defects in hypophosphatasia establishes a role of ALP in skeletal mineralization, the precise function remains unclear. The initial site of mineralization (primary mineralization) normally occurs within the lumen of TNSALP-rich matrix vesicles (MVs) of growth cartilage, bone, and dentin. We investigated whether defective calcification in hypophosphatasia is due to a paucity and/or a functional failure of MVs secondary to TNSALP deficiency. Nondecalcified autopsy bone and growth plate cartilage from five patients with perinatal (lethal) hypophosphatasia were studied by nondecalcified light and electron microscopy to assess MV numbers, size, shape, and ultrastructure and whether hypophosphatasia MVs contain apatite-like mineral, as would be the case if these MVs retained their ability to concentrate calcium and phosphate internally despite a paucity of TNSALP in their investing membranes. We found that hypophosphatasia MVs are present in approximately normal numbers and distribution and that they are capable of initiating internal mineralization. There is retarded extravesicular crystal propagation. Thus, in hypophosphatasia the failure of bones to calcify appears to involve a block of the vectorial spread of mineral from initial nuclei within MVs, outwards, into the matrix. We conclude that hypophosphatasia MVs can concentrate calcium and phosphate internally despite a deficiency of TNSALP activity.
Apatites↗
Juvenile Paget disease: life-long features of a mildly affected young woman.
Unusually mild Juvenile Paget Disease (JPD) was extensively investigated in a mentally retarded 21-year-old white woman. Progressive bowing deformitity of her lower limbs began at age 1 1/2 years. Nontraumatic fractures of both femora and both tibias occurred between ages 9 and 14 years. During adulthood, cortical thickening, osteosclerosis, and bowing affected these bones. Serum alkaline phosphatase (ALP) activity was persistently elevated. We found her serum osteocalcin and urinary hydroxyproline and pyridinoline/deoxypyridinoline to also be increased. The iliac crest histology, at ages 14 and 21 years, showed wide cortices and enhanced skeletal remodeling yet the bone was exclusively lamellar. Features of classic Paget Bone Disease (PBD)--such as hypermultinucleated osteoclasts, peritrabecular fibrosis, and mosaic or woven bone--were absent. Electron microscopy revealed no cytoplasmic or nuclear inclusions. Her dermal fibroblasts in culture synthesized unremarkable levels of ALP with proper membrane topography and lipid anchoring; ALP released into the medium also appeared normal. Six months of synthetic human calcitonin therapy daily appeared to reduce here lower limb pain and warmth, but the radiographs, biochemical parameters of skeletal turnover, and bone scintigraphy were unaltered. Lamellar bone has been reported in JPD but accompanied by excessive amounts of woven bone. Our patient reveals that lamellar bone without features of PBD can characterize the skeletal histopathology of the especially rare case of mild JPD.
Adult↗
Doubling skeletal mass during adult life: the syndrome of diffuse osteosclerosis after intravenous drug abuse.
A former intravenous substance abuser, seropositive for hepatitis C virus infection, was referred for diffuse osteosclerosis. There was no history of fracture or skeletal deformity. Cortical and trabecular bone density was approximately twice the mean value for controls. Skeletal histology revealed dense lamellar bone. Recognized causes of acquired generalized osteosclerosis or hyperostosis were excluded. This patient verifies the syndrome of painful diffuse osteosclerosis after intravenous drug abuse and shows that skeletal mass can be markedly increased with histologically normal, structurally sound bone during adult life. Elucidation of the etiology and pathogenesis could offer an effective treatment for osteoporosis.
Absorptiometry, Photon↗
Absence of paramyxo virus transcripts in juvenile Paget bone disease.
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Child↗
Creatine kinase brain isoenzyme (BB-CK) presence in serum distinguishes osteopetroses among the sclerosing bone disorders.
Creatine kinase (CK) isoenzyme BB-CK is predominantly found in brain and is not normally detected in the blood. A few recent reports, however, have described BB-CK in serum from several patients with osteopetrosis (OP). To evaluate the presence and specificity of BB-CK in serum in the osteopetroses among disorders that increase skeletal mass, we quantitated total CK activity and CK isoenzymes in 15 patients representing the five major clinical forms of OP (2 infantile, 3 intermediate, 7 adult [2 type I, 5 type II], and 3 carbonic anhydrase II [CA II] deficiency cases) and in 22 patients representing 14 other types of sclerosing bone disease. All OP patients (except the two adult type I subjects) had BB-CK readily detected in their serum. Conversely, only 1 of the 22 patients with other sclerosing bone disorders had detectable BB-CK in serum (1 of 3 patients with fibrodysplasia [myositis] ossificans progressiva who had barely measurable activity). In three OP patients (one of two with the infantile form and two of five with adult, type II disease), BB-CK values were sufficiently high that serum total CK activity was elevated. In a newborn with malignant OP, both cord blood plasma and peripheral blood serum had substantial amounts of BB-CK. In three subjects (with adult type II OP), who were restudied 2-6 years later, BB-CK was still elevated in their blood. BB-CK in serum appears to distinguish the osteopetroses among the sclerosing bone disorders. Absence of serum BB-CK in adult type I disease suggests that this condition may not be a genuine form of OP. Assay of BB-CK in fetal blood could be studied as a means for prenatal diagnosis of malignant OP. Why the osteoclast failure that characterizes all true forms of OP is associated with BB-CK in the circulation is a new question for skeletal biologists.
Adolescent↗
Construction of a YAC contig and an STS map spanning 3.6 megabase pairs in Xp22.1.
We have constructed a 3.6 Mb sequence tagged sites (STS)-based yeast artificial chromosome (YAC) contig, consisting of 58 individual YAC clones, spanning the region PDHA1 and DXS451 on Xp22.1. In addition to establishing the order of PDHA1, ISPK-1, DXS2504, DXS1528 and the 13 known polymorphic loci as Xpter-PDHA1-DXS443-DXS3424-ISPK-1-DXS12 29-DXS2504-DXS1528-DXS365-DXS7101- DXS1683-DXS1052-DXS274-DXS92-DXS1226-DX S41-DXS989-DXS451-Xcen, we have also developed 35 novel STSs from YAC end clones. These results provide a high density of STS markers (approximately 1 per 70 kb). Furthermore, a detailed long-range restriction map of the contig has been constructed with rare-cutter enzymes and this has refined and verified the physical distances between markers inferred from YAC sizes and their STS content. The integration of the physical mapping data with previous genetic mapping data and the use of STSs and non-chimeric YAC clones reported here should facilitate the construction of a transcript map of this region and the positional cloning of disease genes in this portion of Xp22.1.
Base Composition↗
Calcium-sensing receptor mutations in familial hypocalciuric hypercalcaemia with recurrent pancreatitis.
OBJECTIVE: Pancreatitis is an unusual complication of the benign disorder familial hypocalciuric hypercalcaemia (FHH) such that it could represent a distinct subgroup of FHH. In order to study this, we investigated three FHH kindreds with recurrent pancreatitis for mutations of the extracellular calcium-sensing receptor (CaR) to identify a possible common genetic aetiology for typical FHH and that associated with pancreatitis. PATIENTS AND METHODS: Three FHH kindreds (18 affected, 14 unaffected members) in which the proband had presented with recurrent pancreatitis were identified. The entire 3234bp coding region of the CaR gene was examined by direct DNA sequencing using fluorochrome labelled dideoxy-terminators. Mutations were confirmed and demonstrated to co-segregate with FHH by restriction enzyme analysis. RESULTS: Three novel heterozygous missense mutations (Asn178Asp, Arg220Gln and Pro221Ser) in the extracellular domain of the CaR were identified in each of the probands. These mutations, which co-segregated with the hypercalcaemia, were not detected as common polymorphisms in 55 unrelated normocalcaemic controls. CONCLUSIONS: Familial hypocalciuric hypercalcaemia with recurrent pancreatitis is associated with calcium-sensing receptor mutations, and thus this variant has the same genetic aetiology as typical familial hypocalciuric hypercalcaemia.
Adult↗
The effect of steam sterilization on the properties of set dental gypsum models.
The aim of this study was to investigate the viability of autoclave sterilization of set dental gypsum models. The effects of autoclaving on the strength, surface hardness and dimensions of specimens of plaster, stone and diestone were investigated. In addition, sodium succinate was used to minimize any changes produced by autoclaving. It has been shown that dental gypsum casts can be successfully steam sterilized. The results showed that for fully-dried gypsum products, autoclaving at 132 degrees C for 5 minutes rendered the casts unacceptable for use. Autoclaving at 121 degrees C for 16 minutes had less effect although casts were still not satisfactory, with the main problems being excessive expansion for plaster and significant strength and surface hardness loss for stone and diestone. The effect of three additional treatment procedures was examined and the least degradation was observed when the casts were soaked in 1 per cent sodium succinate solution and dried prior to autoclaving, then soaked in water immediately after. Using this procedure the average change in properties for plaster, stone and diestone respectively were: loss of strength 36, 21 and 28 per cent, loss of surface hardness 34, 21 and 33 per cent, and linear expansion 0.05, 0.09 and 0.13 per cent. Further refinement may improve the procedure.
Calcium Sulfate↗
X-linked hypophosphatemia: a search for gender, race, anticipation, or parent of origin effects on disease expression in children.
X-Linked hypophosphatemia (XLH) is a sex-linked dominant disorder. It is possible that females are more mildly affected than males. No information is available regarding other potential genetic influences on XLH expression in patients, such as race, anticipation, parent of origin, or molecular heterogeneity. We investigated the above potential genetic influences on XLH expressivity using data from 116 pediatric patients. To compare biochemical parameters, we used data from the 30 prepubertal children (23 girls and 7 boys) selected because they had been without medical therapy for at least 3 months (25 of 30 never treated). To compare height z-scores, we used data from the 27 patients (pre- or postpubertal) selected because they had never received medical or surgical treatment. Ascertainment bias (i.e. referral of girls who were severely affected) was not apparent (observed female/male ratio, 1.64; expected, 2.00; P = 0.29). Parameters of mineral homeostasis did not show statistically significant differences between girls vs. boys, sporadic vs. multigenerational cases (except lower fasting serum phosphate levels in sporadic cases; mean +/- SEM, 2.68 +/- 0.10 vs. 3.02 +/- 0.04 mg/dL; P = 0.049), blacks vs. whites, or for the girls for whom affected fathers vs. mothers transmitted the disorder. Height z-scores correlated with renal phosphate reclamation (i.e. tubular maximum of phosphorus/glomerular filtration rate; r = 0.68; P = 0.014), but were not different for the groupings above. Furthermore, we found no evidence for meiotic drive or for a parental age effect to explain the 18.3% of patients that were new mutations for XLH. Our data fail to show any evidence for genetic heterogeneity or for gender, race, anticipation, or parent of origin effects on XLH expression in children. Despite the recent discovery of a gene (PEX) that is mutated in XLH, the sex-linked dominant phenotype and apparent absence of a gene dose effect in XLH expression in children require explanation.
Black People↗
Hypophosphatasia: levels of bone alkaline phosphatase immunoreactivity in serum reflect disease severity.
Hypophosphatasia is a rare metabolic bone disease characterized biochemically by deficient enzymatic activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). All isoforms of TNSALP (e.g. bone and liver TNSALP), apparently differing only by posttranslational modifications, are affected. To explore the biochemical basis and extremely variable severity of hypophosphatasia, we used 2-site immunoradiometric assays that quantify in serum either 1) bone TNSALP (iBALP) alone, or 2) both bone and liver TNSALP (iTNSALP). Sera from 33 patients in 26 kindreds reflecting all 6 clinical types of the disorder were studied. In every patient, except the two with pseudohypophosphatasia, serum iBALP and iTNSALP levels were decreased compared to age-appropriate control ranges. The magnitude of the decrease in iBALP and iTNSALP levels correlated with clinical severity. The mean ratio of iBALP or iTNSALP level to total ALP activity was unremarkable for the mild childhood, adult, and odonto forms of hypophosphatasia. For the severe perinatal and infantile forms, the mean ratios were low. If our finding of reduced iBALP levels in the circulation reflects a similar abnormality in the skeleton, the pathogenesis of hypophosphatasia could involve decreased amounts of extracellular TNSALP in bone and cartilage. How TNSALP gene mutations affect the enzyme and cause skeletal disease requires further investigation.
Adult↗