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The cure of osteopetrosis by allogenic bone marrow injection has been obtained in homozygous rats for both mutations, osteopetrosis (op) and athymic nude (rnu). This new animal model will help in studying the eventual relationship between the bone resorption process and the immunological reconstitution.
Osteopetrosis, a group of highly heterogeneous genetic bone disorders, is characterized by deafness, increased bone density, hepatosplenomegaly, pancytopenia and intellectual disability. Osteopetrosis can be divided into three subtypes: autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IARO), and autosomal dominant osteopetrosis (ADO). CLCN7 has been reported to be the most common gene responsible for the ADO-II subtype. In this study, a novel variant, c.175dupA (p.Met59Asnfs*8), of CLCN7 was identified in a Chinese Han consanguineous family with suspected ADO-II. The proband was homozygous for the p.Met59Asnfs*8 variant and exhibited multiple severe phenotypes, including deafness, short stature, brittle bones, optic atrophy, hepatosplenomegaly, intellectual disability, cleft palate and recurrent infection. However, except for the mother of the proband, who presented a series of clinical phenotypes caused by bone marrow failure, all the other family members who were heterozygous had no obvious abnormal phenotypes. Our study suggested that the novel variant p.Met59Asnfs*8 in CLCN7 was very likely pathogenic factor in our suspected ADO-II family. The phenotypes of heterozygous carriers may be affected by incomplete penetrance. Loss of function of CLCN7 caused by nonsense-mediated mRNA decay (NMD) due to the frameshift variant was likely the underlying pathogenic mechanism. This study broadened the mutation spectrum of CLCN7, provided a foundation for timely and effective clinical intervention for related diseases, and demonstrates the importance of genetic counselling.
Osteoclast have been observe for the first time in toothless (t1) rats, a mutation with inherits osteopetrosis as an autosomal recessive. The ability of t1 rats to raise the serum calcium concentration after injection of parathyroid extract was severely limited when compared with normal littermates. In addition, osteopetrosis in t1 rats is not cured by radiation and infusion of normal spleen or bone marrow cells from normal littermates, a method know to cure osteopetrosis in mutants of this and other species. This indirect evidence for a reduction in bone resorption as a cause of osteopetrosis in this mutation and the failure of transplanted cells to cure the disease are discussed in relation to the development and function of osteoclasts.
We present the clinical and electrophysiological findings in three cases of osteopetrosis with visual loss. In all cases the findings on electroretinography suggested diffuse retinal degeneration, despite normal ophthalmoscopic appearance of the retinas. We suggest that retinal degeneration may be a common finding in osteopetrosis and a major cause of visual loss. Patients with osteopetrosis and poor vision should be examined using electrophysiological techniques to detect unsuspected retinal dysfunction.
Osteopetrosis is an unusual bone disorder in which the skeleton is radiographically dense. The condition is conventionally subclassified into a benign autosomal dominant adult form and a malignant autosomal recessive variety. Among 14 affected individuals whom we have studied, 4 adults had an intermediate type of osteopetrosis in which serious complications included osteomyelitis, pathological fractures and dyshaemopoiesis. The fundamental biochemical relationship of this disorder with the classic forms of osteopetrosis is uncertain. The osteopetroses must be distinguished from other sclerosing bone conditions which have a different course and prognosis. Sclerosteosis and craniometaphyseal dysplasia, both of which occur in South Africa, are of practical importance in this context.
Spleen cells from normal rats are known to cure osteopetrosis in ia littermates within 3 weeks. In this study cell suspensions from liver, thymus, bone marrow, salivary gland, skeletal muscle and brain from normal rats were tested for their ability to cure osteopetrosis in ia littermates whose ability to reject these cells had been suppressed by whole-body irradiation. Cells from liver, thymus and bone marrow cured the disease as effectively as spleen cells from normal littermates. Mutants that received cells from salivary gland, muscle and brain remained osteopetrotic. These data suggest that some cell found in spleen, liver, thymus and bone marrow of 10-day-old normal rats, such as a lymphoid cell or stem cell, can restore hemopoiesis and bone resorption in osteopetrotic (ia) rats.
The recessive genes mi and gl in the homozygous state determine, among other phenotypic effects, osteopetrosis in the house mouse. From a stock carrying mi derived from Grüneberg (1963) the mi gene was bred into the standard CBA/H inbred strain. Microphthalmic mice of these two stocks and their hybrids were treated as newborn by intraperitoneal injection and at weaning or maturity by intravenous injection of cell suspensions containing hematopoietic stem cells from phenotypically normal mice. Resolution of much of the osteopetrosis but not the other phenotypic effects occurred within a few months in the majority of cases, provided syngeneic or H-2 compatible allogeneic cells were given: it did not occur spontaneously or on giving H-2 incompatible cells or on giving compatible material by an inappropriate route. The results accord with hypotheses that (1) osteoclasis of scaffoldtype woven bone is impaired in mi mi, (2) that osteoclastic cells are derived through circulating monocytes from hematopoietic stem cells, and (3) in mi mi this defect can be overcome by a transplant of normal hemopoietic stem cells.
The characteristic feature of osteopetrosis is a lack of osteoclastic activity, leading to a series of somatic problems for afflicted persons. The life span of osteopetrotic patients has increased in recent years, thereby making oral aspects of the disease more evident. Four children with malignant osteopetrosis, born between 1967 and 1975, were examined. In all patients the anterior teeth were of normal shape, and erupted on schedule. Primary molars and all permanent teeth were greatly distorted, and remained totally or partly embedded in basal bone. Vertical growth of alveolar ridge was very limited. Where a fenestration of overlaying mucosa had occurred, a localized progressive osteitis developed, leading to soft tissue inflammation and, in two cases, extraoral mandibular fistulas. Peridontal attachment was very poor, spontaneous exfoliation had occurred in all patients. In two children tooth germs and necrotic bone were surgically removed. No beneficial effect of the treatment was observed. Large doses of antibiotics were needed to control recurring infections. No means of curing progressive osseous destruction of mandibular bone has been found. The general prognosis is poor.
Chicks infected as 12-day-old embryos with an end-point purified derivative of avian myeloblastosis virus developed a rapidly progressive osteopetrosis that manifested within 1 week of hatching. A detailed comparison of osteopetrotic chicks and normal hatchmates revealed the following. (i) Osteopetrotic chicks exhibited a stunting syndrome, growing at a mean rate that was 26% of the control rats. (ii) At autopsy, the mass of the lymphoid organs was reduced, whereas the mass of the heart, pancreas, kidneys, lungs, brain, liver, and bones of osteopetrotic chicks was increased. Edema was likely responsible for most of the increase in organ weight. (iii) Infected chicks exhibited a normochromic, normocytic anemia that was virus dose dependent and was not required for the development of osteopetrosis. (iv) Bone collagen content was normal. (v) Osteopetrotic bone was initially hypomineralized, but later became more fully mineralized. (vi) The concentrations of alpha, beta, and gamma globulins in the plasma were elevated in osteopetrotic chicks, whereas albumin concentration was decreased. (vii) The level of plasma alkaline phosphatase was elevated in osteopetrotic chicks, yet the level of acid phosphatase was unchanged. (viii) Body and bone temperatures were unchanged.
Myeloblastosis-associated virus (MAV)-2(0), a virus which was derived from avian myeloblastosis virus and induced a high incidence of osteopetrosis, was compared with avian lymphomatosis virus 5938, a recent field isolate which induced a high incidence of lymphomatosis. The following information was obtained. (i) MAV-2(0) induced osteopetrosis, nephroblastoma, and a very low incidence of hepatocellular carcinoma. No difference was seen in the oncogenic spectrum of end point and plaque-purified MAV-2(0). (ii) 125I-labeled RNA sequences from MAV-2(0) formed hybrids with DNA extracted from osteopetrotic bone at a rate suggesting five proviral copies per haploid cell genome. The extent of hybridization of MAV-2(0) RNA with DNA from osteopetrotic tissue was more extensive (87%) than was observed in reactions with DNA from uninfected chicken embryos (52%). (iii) Competition of unlabeled viral RNA in hybridization reactions between the radioactive RNA from the two viruses and their respective proviral sequences present in tumor tissues showed that 15 to 20% of the viral sequences detected in these reactions were unshared. In contrast, no differences were detected in competition analyses of RNA sequences from the two viruses detected in DNA of normal chicken cells. (iv) MAV-2(0) 35S RNA was indistinguishable in size from avian lymphomatosis virus 5938 35S RNA by polyacrylamide gel electrophoresis.
Malignant osteopetrosis is the autosomal recessive form of osteopetrosis. Besides anemia, hepatosplenomegaly, and the osteopetrotic bone seen on roentgenogram, the head and neck manifestations are important to the diagnosis and clinical course of this disease. Eye, ear, nose, face, teeth, mandible, maxilla, central nervous system structures, and cranial nerves are often involved.
The "osteopetrosis" section of the Fairbank Collection in the Radiology Museum of the Royal National Orthopaedic Hospital contains radiographs and case notes of twenty-two patients. This material has been reviewed in terms of modern concepts in an attempt to obtain a long-term follow-up and a firm diagnosis in each individual. Nine patients proved to have the classical autosomal dominant form of osteopetrosis, four had the malignant autosomal recessive type, craniometaphyseal dysplasia was present in two kindreds and isolated individuals had pyknodysostosis, atypical craniodiaphyseal dysplasia and craniosclerosis with osteopathia striata. As these conditions differ greatly in their clinical and genetic prognoses, diagnostic categorisation is of practical importance.
Osteopetrosis is a unique model for investigating osteoclast formation from lymphocytes and more precisely from T-lymphocytes. In the pathogenesis of this condition, a thymic impairement must be postulated. The cure of several osteopetrotic animal mutants and an infant suffering from juvenile malignant osteopetrosis by injecting normal marrow are the first examples of the successful management of a bone disorder by cell injection.
Since infants with malignant osteopetrosis often die from infection at an early age, we studied several aspects of host defense in five such infants. No consistent abnormality was found in cellular or humoral immunity. Monocyte cellular chemotaxis and phagocytosis were normal in four tested infants. However, all four of these infants had decreased intracellular bacterial killing by monocytes. Neutrophil function tests in five infants showed that two had defective bacterial phagocytosis and four had reduced cellular chemotaxis, decreased nitroblue tetrazolium reduction, and decreased intracellular bacterial killing. The severity of the decreased bactericidal capacity of granulocytes did not correlate with the number of circulating immature granulocytes. Our data suggest that abnormal function of circulating monocytes and granulocytes may contribute to impaired host resistance to infection. We postulate that this defect may reflect a more generalized inherited abnormality of phagocytic cells and perhaps osteoclasts that plays a role in the pathogenesis of infantile osteopetrosis.
Chickens infected intravenously at 8 days after hatching with an avian osteopetrosis virus developed a severe, progressive anemia in the absence of osteopetrosis. The anemia was characterized as a pancytopenia, in which erythrocytes, granulocytes, and thrombocytes decreased concomitantly. Serum bilirubin levels were normal, whereas erythrocytes from infected chickens demonstrated a slightly elevated osmotic fragility. A negative Coombs test indicated that there was no evidence for erythrocyte-bound antibody. Erythrocytes from infected animals had slightly decreased 51Cr-labeled erythrocyte survival time when compared with normal. Examination of marrow histological preparations, together with ferrokinetic studies with 59Fe, indicated that marrow failure occurred during the acute phase of the anemia. Circulating virus was present during the development and acute phases of the anemia, but disappeared during the recovery phase of the disease. Neutralizing antibody appeared after the disappearance of circulating virus. It is concluded that virus infection induced both marrow failure (aplastic crisis) and decreased erythrocyte survival.
Autosomal dominant osteopetrosis (ADO) is a rare osteosclerotic disorder usually caused by missense variants in the CLCN7 gene, which results in impaired osteoclastic bone resorption. Penetrance is incomplete, and disease severity varies widely, even among relatives within the same family. Although ADO can cause visual loss, osteonecrosis, osteomyelitis, and bone marrow failure, the most common complication of ADO is fracture. We are conducting a natural history study to characterize disease progression and determinants of disease severity. We hypothesized that baseline BMD and bone turnover markers would correlate with self-reported fracture history. We report cross-sectional analysis of baseline data from the natural history study in 54 individuals (42 adults, 12 children). In adults, Z-scores for both volumetric (r = 0.87, p < .001) and areal BMD (aBMD) of the LS, and Z-scores for FN, and TH aBMD (r = 0.77 to 0.78; p < .001) were correlated with lifetime fracture number. Tartrate resistant acid phosphatase, a marker of osteoclast number, correlated positively with fracture (r = 0.52, p = .004) consistent with an adaptive response of higher numbers of osteoclasts among more severely affected individuals. However, fracture number correlated inversely with the bone resorption markers serum C-telopeptide (r = -0.60, p < .001) and urine N-telopeptide/creatinine ratio (r = -0.35, p = .047), suggesting that ADO subjects who have the most reduced osteoclast activity have a greater tendency to fracture. Correlation coefficients between fractures, BMD, and bone turnover markers were similar when limited to the 37 adults with disease-causing CLCN7 variants. There were no statistically significant differences between subjects with the most common CLCN7 variant (G215R), the most common variant in our cohort, compared to other CLCN7 variants with respect to fracture, bone density measures, or biochemical markers of bone turnover. These data demonstrate that bone density and biochemical bone turnover markers are indicators of ADO severity as defined by fracture number.
Indices of calcium and phosphorus metabolism were studied in 3 children with osteopetrosis before and after infusion of bovine parathyroid hormone extract. Basal plasma concentrations of calcium, alkaline phosphatase and 25-hydroxy vitamin D tended to be low. Plasma immunoreactive PTH levels were at the upper normal range in two patients. A marked increase in urinary cyclic AMP in all patients was solely due to an increase in the nephrogenous cAMP. After vitamin D treatment urinary cAMP was essentially unchanged with the same preponderance of nephrogenous cAMP. Following PTH infusion plasma cAMP showed a brisk rise. There was also a prompt rise in urinary cAMP and a distinct decrease in the calcium to sodium clearance ratio indicating increased calcium reabsorption. Phosphaturic effect was only observed when PTH was given in the highest dose level. The findings are consistent with a state of low grade hyperparathyroidism which could not be related to the plasma levels of 25-hydroxy vitamin D or calcium.
The following report concerns a case of malignant osteopetrosis associated with hypocalcemic rickets unresponsive to vitamin D. Parathyroid hormone (PTH) and Calcitonin (CT) secretions were studied in basal conditions and under calcium gluconate infusion, before and after high doses of vitamin D. Basal values (PTH: 690 pg Eq/ml; CT: 560 pg/ml) were found to be much higher than in five control subjects of the same age group, even after vitamin D therapy (PTH: 990 pg Eq/ml; CT:450 pg/ml). Like rickets, PTH and CT secretions do not seem, therefore, to be notably influenced by vitamin D therapy.