Increased urine heparan and chondroitin sulphate excretion in patients with osteopetrosis.
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Adolescent↗
Biomedical subjects
M P Whyte
Publications and source records attributed to M P Whyte.
Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.
Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.
Base Sequence↗
Mild autosomal dominant hypophosphatasia: in utero presentation in two families.
We describe four pregnancies in two families in which mild hypophosphatasia, apparently transmitted as an autosomal dominant trait, manifested in utero as severe long bone bowing. Postnatally, there was spontaneous improvement of the skeletal defects. Recognition of this presentation for hypophosphatasia by family investigation and assessment of the fetal skeleton for degree of ossification and chest size using ultrasonography is important. The prognosis for this condition is considerably better than for more severe forms of hypophosphatasia and for many other disorders that cause skeletal defects with long bone bowing in utero.
Adult↗
Mild hypophosphatasia mimicking severe osteogenesis imperfecta in utero: bent but not broken.
We describe a fifth instance of hypophosphatasia presenting with prenatal findings suggestive of a very severe bone dysplasia but with a subsequently benign course. Spontaneous improvement of long-bone angulation began prenatally. The postnatal course has been encouraging. This sixth clinical form of hypophosphatasia, which we suggest should be called the benign prenatal form of hypophosphatasia, should be added to the differential diagnostic possibilities considered when angulation or bowing of long bones is discovered prenatally.
Adult↗
Transcription map of Xq27: candidates for several X-linked diseases.
Human Xq27 contains candidate regions for several disorders, yet is predicted to be a gene-poor cytogenetic band. We have developed a transcription map for the entire cytogenetic band to facilitate the identification of the relatively small number of expected candidate genes. Two approaches were taken to identify genes: (1) a group of 64 unique STSs that were generated during the physical mapping of the region were used in RT-PCR with RNA from human adult and fetal brain and (2) ESTs that have been broadly mapped to this region of the chromosome were finely mapped using a high-resolution yeast artificial chromosome contig. This combined approach identified four distinct regions of transcriptional activity within the Xq27 band. Among them is a region at the centromeric boundary that contains candidate regions for several rare developmental disorders (X-linked recessive hypoparathyroidism, thoracoabdominal syndrome, albinism-deafness syndrome, and Borjeson-Forssman-Lehman syndrome). Two transcriptionally active regions were identified in the center of Xq27 and include candidate regions for X-linked mental retardation syndrome 6, X-linked progressive cone dystrophy, X-linked retinitis pigmentosa 24, and a prostate cancer susceptibility locus. The fourth region of transcriptional activity encompasses the FMR1 (FRAXA) and FMR2 (FRAXE) genes. The analysis thus suggests clustered transcription in Xq27 and provides candidates for several heritable disorders for which the causative genes have not yet been found.
Chromosome Mapping↗
Measles virus nucleocapsid transcript expression is not restricted to the osteoclast lineage in patients with Paget's disease of bone.
Abundant evidence supports a viral etiology for Paget's disease of bone (PD), however, an infectious virus has not been isolated from PD patients. Thus, it is unclear how the virus is maintained for the many years that the disease persists in patients. We considered if a primitive multipotential hematopoietic stem cell (HSC), which is self-renewing, passes the virus to its differentiated progeny and serves as a reservoir for the pathogen. If a primitive stem cell harbored measles virus (MV), then other hematopoietic lineages derived from this stem cell in PD patients should also express MV transcripts. Therefore, because the human hematopoietic stem cell has not been clearly identified or isolated in large numbers, we isolated RNA from highly purified erythroid and multipotential hematopoietic progenitors that are the precursors for erythroid, granulocyte, megakaryocyte and macrophages (CFU-GEMM), and used RT-PCR to determine if MV nucleocapsid transcripts were present. MV transcripts were detected in PD patients in early erythroid (BFU-E) and more primitive multipotential myeloid progenitors (CFU-GEMM). Nonhematopoietic stromal cells from PD patients did not express MV transcripts. The expression of MV transcripts in erythroid progenitors was further confirmed by in situ hybridization using antisense riboprobes to MV nucleocapsid transcripts. Thus, our findings suggest that the pluripotent HSCs may be a potential reservoir for the virus. We propose that when HSCs, which contain MV, divide they produce a second HSC that serves as a reservoir for the virus and also transmit the virus to their more differentiated progeny in the erythroid and myeloid lineages. This mechanism would permit a defective virus to persist in HSCs of PD patients for many years, since HSCs are usually in G0 phase, and then be transmitted to more differentiated cells. This model further suggests that a mature complete virus that affects cell function could only act pathogenetically in the osteoclast lineage, which offers a permissive milieu.
Antigens, CD34↗
Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13.
Calcium homeostasis by the kidneys and parathyroids is mediated by the calcium-sensing receptor (CaSR), which is located on 3q21-q24 and belongs to family C of the superfamily of G-protein coupled receptors that includes those for metabotropic glutamate, certain pheromones, and gamma-amino butyric acid (GABA-B). Inactivating CaSR mutations result in familial benign hypercalcemia (FBH), or familial hypocalciuric hypercalcemia (FHH), whereas activating mutations result in hypocalcemic hypercalciuria. However, not all FBH patients have CaSR mutations, which, together with the mapping of another FBH locus to 19p13.3, suggests that additional CaSRs or second messengers may be involved. These may be identified by positional cloning, and we therefore performed a genomewide search, using chromosome-specific sets of microsatellite polymorphisms, in an Oklahoma family with an FBH variant (FBHOk), for which linkage to 3q and 19p had been excluded. Linkage was established between FBHOk and eight chromosome 19q13 loci, with the highest LOD score, 6.67 (recombination fraction.00), obtained with D19S606. Recombinants further mapped FBHOk to a <12-cM interval flanked by D19S908 and D19S866. The calmodulin III gene is located within this interval, and DNA sequence analysis of the coding region, the 5' UTR, and part of the promoter region in an individual affected with FBHOk did not detect any abnormalities, thereby indicating that this gene is unlikely to be implicated in the etiology of FBHOk. This mapping of FBHOk to chromosome 19q13 will facilitate the identification of another CaSR or a mediator of calcium homeostasis.
Calcium↗
X-linked recessive spondyloepiphyseal dysplasia tarda. Clinical and radiographic evolution in a 6-generation kindred and review of the literature.
We characterize the clinical and radiographic evolution of X-linked recessive spondyloepiphyseal dysplasia tarda (SEDT) in a 6-generation kindred from Arkansas (SEDT(AK)). Our observations show the natural progression of SEDT(AK) and enable carrier detection by radiographic study. We find that, SEDT(AK) manifests as a postnatal defect. Affected hemizygous males can have radiographically normal vertebrae at birth. The pathogenesis seems to involve a developmental disturbance in endochondral bone formation that is reflected most dramatically in vertebrae by a radiographically inapparent ring apophysis. This defect leads to distinctive malformation of the anterior margins of the lumbar vertebrae during childhood. Subsequently, there is degeneration of intervertebral discs and destruction of spinal facet joints. In the femur, the head, neck, and distal condyles are abnormally shaped and become distorted so that osteoarthritis of the hip is not uncommon. Obligate carrier females heterozygous for the SEDT(AK) gene defect demonstrate several similar but more subtle skeletal abnormalities beginning in early adult life. These women seem to be troubled frequently by arthralgia by middle age. The cumulative findings in SEDT(AK) implicate a defect in a gene at Xp22.2-22.1 that engenders a relatively mild disturbance in endochondral bone formation, especially in the axial skeleton. Accounts of large, well-characterized SEDT kindreds remain essential to appreciate fully any interfamily variability of disease expression and to understand better the pathogenesis of the SEDT defect on the X chromosome.
Adult↗
Hyperparathyroidism and increased serum IGF-binding protein-2 levels in hepatitis C-associated osteosclerosis.
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Aged↗
Alkaline phosphatase knock-out mice recapitulate the metabolic and skeletal defects of infantile hypophosphatasia.
Hypophosphatasia is an inborn error of metabolism characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) and skeletal disease due to impaired mineralization of cartilage and bone matrix. We investigated two independently generated TNSALP gene knock-out mouse strains as potential models for hypophosphatasia. Homozygous mice (-/-) had < 1% of wild-type plasma TNSALP activity; heterozygotes had the predicted mean of approximately 50%. Phosphoethanolamine, inorganic pyrophosphate, and pyridoxal 5'-phosphate are putative natural substrates for TNSALP and all were increased endogenously in the knock-out mice. Skeletal disease first appeared radiographically at approximately 10 days of age and featured worsening rachitic changes, osteopenia, and fracture. Histologic studies revealed developmental arrest of chondrocyte differentiation in epiphyses and in growth plates with diminished or absent hypertrophic zones. Progressive osteoidosis from defective skeletal matrix mineralization was noted but not associated with features of secondary hyperparathyroidism. Plasma and urine calcium and phosphate levels were unremarkable. Our findings demonstrate that TNSALP knock-out mice are a good model for the infantile form of hypophosphatasia and provide compelling evidence for an important role for TNSALP in postnatal development and mineralization of the murine skeleton.
Age Factors↗
Polycystic bone disease: A new, autosomal dominant disorder.
We describe a new heritable bone disease characterized radiographically by increasingly numerous and enlarging cyst-like lesions throughout the skeleton. Beginning in early childhood, a father, son, and daughter all suffered from progressively frequent pathological fractures involving such radiolucencies. Healing occurred uneventfully and with little residual pain or deformity. Biochemical parameters of mineral homeostasis and skeletal turnover were normal. Bone scanning showed increased radioisotope uptake primarily in fractures and in the largest collections of the lesions. The histopathology is uncertain, but may reflect a form of intraosseous lipomatosis. This unique condition, which we have provisionally named polycystic bone disease, is inherited as an autosomal dominant trait with a high degree of penetrance.
Bone Cysts↗
Bilateral radial ray hypoplasia with multiple epiphyseal dysplasia.
We describe a 5-4/12-year-old girl with the unique combination of bilateral radial ray hypoplasia and multiple epiphyseal dysplasia (MED). Radial ray hypoplasia was diagnosed at birth. MED was documented at age 4-3/12 years when she presented with leg pain and short stature and was found to have femoral anteversion and tibial torsion giving rise to severe genu valgum deformity and intoeing. She has no facial anomalies and is developmentally normal. Family history is unremarkable and chromosomal analysis was normal. Investigation of mineral metabolism showed idiopathic hypercalciuria. Surgical lengthening of her severely hypoplastic left radius at age 19 months was successful. Bilateral femoral and tibial osteotomies at age 5-4/12 years corrected her lower limb deformities. This combination of two distinctive but rare skeletal abnormalities may represent a new syndrome.
Abnormalities, Multiple↗
Insulin-like growth factor system abnormalities in hepatitis C-associated osteosclerosis. Potential insights into increasing bone mass in adults.
Hepatitis C-associated osteosclerosis (HCAO) is a rare disorder characterized by a marked increase in bone mass during adult life. Despite the rarity of HCAO, understanding the mediator(s) of the skeletal disease is of great interest. The IGFs-I and -II have potent anabolic effects on bone, and alterations in the IGFs and/or IGF-binding proteins (IGFBPs) could be responsible for the increase in bone formation in this disorder. Thus, we assayed sera from seven cases of HCAO for IGF-I, IGF-II, IGF-IIE (an IGF-II precursor), and IGFBPs. The distribution of the serum IGFs and IGFBPs between their ternary ( approximately 150 kD) and binary (approximately 50 kD) complexes was also determined to assess IGF bioavailability. HCAO patients had normal serum levels of IGF-I and -II, but had markedly elevated levels of IGF-IIE. Of the IGFBPs, an increase in IGFBP-2 was unique to these patients and was not found in control hepatitis C or hepatitis B patients. IGF-I and -II in sera from patients with HCAO were carried, as in the case of sera from control subjects, bound to IGFBP-3 in the approximately 150-kD complex, which is retained in the circulation. However, IGF-IIE was predominantly in the approximately 50-kD complex in association with IGFBP-2; this complex can cross the capillary barrier and access target tissues. In vitro, we found that IGF-II enhanced by over threefold IGFBP-2 binding to extracellular matrix produced by human osteoblasts and that in an extracellular matrix-rich environment, the IGF-II/IGFBP-2 complex was as effective as IGF-II alone in stimulating human osteoblast proliferation. Thus, IGFBP-2 may facilitate the targeting of IGFs, and in particular IGF-IIE, to skeletal tissue in HCAO patients, with a subsequent stimulation by IGFs of osteoblast function. Our findings in HCAO suggest a possible means to increase bone mass in patients with osteoporosis.
Alkaline Phosphatase↗
Differing lumbar vertebral mineralization rates in ambulatory pediatric patients with osteogenesis imperfecta.
The purpose of this study was to evaluate serial changes in bone mineral density (BMD) of the lumbar spine in individual children and adolescents with untreated osteogenesis imperfecta (OI) using dual X-ray absorptiometry (DXA). Twenty-seven pediatric patients with OI who had no historical or radiographic evidence of lumbar fracture, required no assistive device for mobility, and were taking no medications known to affect skeletal mineralization during the study period comprised the investigational group. Absolute BMD and age- and gender-matched BMD (Z-scores) were assessed relative to standard parameters of growth (height, weight, age, height adjusted for age and gender and body surface area) and severity of disease (lifetime fracture rate). The spinal mineralization rate (SMR) between examinations for 15 patients with more than one measurement (n = 20 intervals) was expressed as the magnitude of the change in BMD Z-score per year. Both BMD and BMD Z-score were closely correlated with height, height Z-score, weight and body surface area and were inversely related to fracture rate (P < 0.001 for all comparisons). BMD was also highly correlated with patient age (P < 0.001). Stepwise regression analysis showed that together height Z-score and lifetime fracture rate improved the prediction of BMD Z-score (r = 0. 71; P < 0.001). SMRs ranged from -0.5 to 3.5. The average change in SMR between sequential measurements was 168% for the five children who had more than two DXA examinations. Linear regression showed a significant negative correlation between SMR and height Z-score (r = -0.79, P < 0.001). We conclude that vertebral body size is a critical determinant of BMD and BMD Z-score in OI because DXA results are expressed per unit area, not per unit volume. Pediatric patients with OI mineralize their lumbar vertebrae at rates similar to healthy children but tend to lag behind in overall mineralization. The rate of mineralization at any age appears to be related to the patient's height (adjusted for age- and gender-matched controls) and inversely related to the patient's lifetime rate of fractures. Our data suggest that vertebral mineralization in children with OI is related primarily to rapid increases in vertebral volume and only secondarily to increases in vertebral mineral density.
Adolescent↗
Severe hypophosphatemia in children with kwashiorkor is associated with increased mortality.
Severe hypophosphatemia, serum phosphate concentration <0.32 mmol/L (<1.0 mg/dL), occurred in 8 of 68 (12%) of children with kwashiorkor within 48 hours of admission; 5 of 8 (63%) of these children died, compared with 13 of 60 (22%) children without severe hypophosphatemia (P <.02). Dermatosis and dehydration were significantly correlated with severe hypophosphatemia, but these clinical signs could not reliably predict fatal cases. Severe hypophosphatemia seems to be common and life-threatening in children with kwashiorkor in Malawi.
Child, Preschool↗
Localisation of X linked recessive idiopathic hypoparathyroidism to a 1.5 Mb region on Xq26-q27.
X linked recessive idiopathic hypoparathyroidism (HPT) has been observed in two kindreds from Missouri, USA. Affected subjects, who are males, suffer from infantile onset of epilepsy and hypocalcaemia, which appears to be the result of an isolated congenital defect of parathyroid gland development; females are not affected and are normocalcaemic. The gene causing HPT has been previously mapped to a 7 cM interval, flanked centromerically by F9 and telomerically by DXS98, in Xq26-q27, and an analysis of mitochondrial DNA has established a common ancestry for these two kindreds. In order to define further the map location of HPT and thereby facilitate its isolation, we have undertaken linkage studies using polymorphic loci whose order has been established as Xcen - DXS1001 - DXS294 - DXS102 - F9 - DXS1232 - DXS984 - CDR1 - DXS105 - DXS1205 - DXS1227 - DXS98 - DXS52 - Xqter, within this region. Our results established linkage (lod score > 3) between HPT and eight of these 12 loci and indicated that the most likely location of HPT was within a 1.5 Mb interval flanked centromerically by F9 and telomerically by DXS984. Thus, the results of this study have helped to refine the map location of HPT, and this will facilitate the identification of this putative developmental gene and its role in the embryological formation of the parathyroids.
Chromosome Mapping↗
Hepatitis C-associated osteosclerosis: late onset after blood transfusion in an elderly woman.
A 69-yr-old woman with hepatitis C virus (HCV) infection from blood transfusion 14 yr earlier was evaluated in 1997 for increasing appendicular skeletal pain. Diffusely elevated radioisotope uptake on bone scanning had appeared during the past 15 months. Radiographs spanning 1978-1997 showed remarkable restoration of bone mass and a skeleton like that of a young woman. Bone mineral densities of the femoral neck and lumbar spine were above the mean peak bone mass of young women (T scores, +1.8 and +1.3, respectively) and 160% and 147% of mean values for age-matched female controls (Z-score, +3.7 and +3.6, respectively). Biochemical markers of skeletal remodeling were substantially increased. Bone marrow biopsy showed normal lamellar bone. Serum alkaline phosphatase activity assays suggested that accelerated skeletal turnover began 6-12 months before symptoms. HC-associated osteosclerosis has been reported in nine individuals 27-73 yr of age, most with a history of i.v. drug abuse. Our patient demonstrates that parenteral exposure to blood rather than illicit drugs is the feature common to all affected subjects. Furthermore, we document that there can be a long latency between HCV infection and the development of skeletal abnormalities. We also find that bone mass can be restored by this disorder in a postmenopausal woman. Routine radiographs, however, may not show overt osteosclerosis in the elderly. The precise pathogenesis of this disorder is unknown. Understanding and control of the mechanism of HC-associated osteosclerosis could potentially lead to correction of low bone mass from osteoporosis with good quality skeletal tissue.
Adult↗