Osteopetrosis, Autosomal Recessive 1

A number sign (#) is used with this entry because of evidence that autosomal recessive osteopetrosis-1 (OPTB1) is caused by homozygous or compound heterozygous mutation in the TCIRG1 subunit (604592) of the vacuolar proton pump on chromosome 11q13.

Description

Osteopetrosis (OPT) is a life-threatening disease caused by subnormal osteoclast function, with an incidence of 1 in 250,000 births. The disease usually manifests in the first few months of life with macrocephaly and frontal bossing, resulting in a characteristic facial appearance. Defective bone remodeling of the skull results in choanal stenosis with concomitant respiratory problems and feeding difficulties, which are the first clinical manifestation of disease. The expanding bone encroaches on neural foramina, leading to blindness, deafness, and facial palsy. Complete visual loss invariably occurs in all untreated patients, and hearing loss is estimated to affect 78% of patients with OPT. Tooth eruption defects and severe dental caries are common. Calcium feedback hemostasis is impaired, and children with OPT are at risk of developing hypocalcemia with attendant tetanic seizures and secondary hyperparathyroidism. The most severe complication of OPT, limiting survival, is bone marrow insufficiency. The abnormal expansion of cortical and trabecular bone physically limits the availability of medullary space for hematopoietic activity, leading to life-threatening cytopenia and secondary expansion of extramedullary hematopoiesis at sites such as the liver and spleen (summary by Aker et al., 2012).

Genetic Heterogeneity of Autosomal Recessive Osteopetrosis

Other forms of autosomal recessive infantile malignant osteopetrosis include OPTB4 (611490), which is caused by mutation in the CLCN7 gene (602727) on chromosome 16p13, and OPTB5 (259720), which is caused by mutation in the OSTM1 gene (607649) on chromosome 6q21. A milder, osteoclast-poor form of autosomal recessive osteopetrosis (OPTB2; 259710) is caused by mutation in the TNFSF11 gene (602642) on chromosome 13q14, an intermediate form (OPTB6; 611497) is caused by mutation in the PLEKHM1 gene (611466) on chromosome 17q21, and a severe osteoclast-poor form associated with hypogammaglobulinemia (OPTB7; 612301) is caused by mutation in the TNFRSF11A gene (603499) on chromosome 18q22. Another form of autosomal recessive osteopetrosis (OPTB8; 615085) is caused by mutation in the SNX10 gene (614780) on chromosome 7p15. A form of autosomal recessive osteopetrosis associated with renal tubular acidosis (OPTB3; 259730) is caused by mutation in the CA2 gene (611492) on chromosome 8q21.

Autosomal dominant forms of osteopetrosis are more benign (see OPTA1, 607634).

Clinical Features

Patients with osteopetrosis display macrocephaly, progressive deafness and blindness, hepatosplenomegaly, and severe anemia beginning in early infancy or in fetal life. Deafness and blindness are generally thought to represent effects of pressure on nerves. (Keith (1968) presented evidence he interpreted as indicating that primary retinal atrophy, not optic atrophy from nerve pressure, occurs in osteopetrosis.) The anemia is caused by encroachment of bone on marrow, resulting in obliteration, and the hepatosplenomegaly is caused by compensatory extramedullary hematopoiesis. The condition results from defective resorption of immature bone. Prenatal diagnosis is possible by x-ray. Enell and Pehrson (1958) described 2 sibs and a cousin affected with the early severe form in a highly inbred kindred. In 2 Palestinian Muslim families that lived in the same village, Dudin and Rambaud-Cousson (1993) found 7 cases of lethal infantile osteopetrosis. In 2 of the 7 persons, short-segment Hirschsprung disease (142623), a probably independent disorder, was also present.

Orchard et al. (1992) found that the serum of 13 patients with what they termed malignant osteopetrosis showed radioimmunoassay levels of CSF1 equal to or higher than control serum. In addition, serum from 6 osteopetrotic patients was tested in a bioassay to determine if the CSF1 present was biologically active; in all cases there was demonstrable activity in these samples.

Diagnosis

Prenatal Diagnosis

Ogur et al. (1995) established the prenatal diagnosis of osteopetrosis at 25 weeks of pregnancy by fetal x-ray evaluation which showed typical changes.

Clinical Management

The occurrence of hypocalcemia and even tetany in cases of osteopetrosis is consistent with a thyrocalcitonin disorder. Moe and Skjaeveland (1969) described beneficial effects of cortisone.

Performing bone marrow transplant (BMT) from an HLA-MLC identical brother, Coccia et al. (1980) demonstrated, in an infant with malignant osteopetrosis, that the disease was greatly ameliorated, Y-bearing osteoclasts (but not osteoblasts) were transferred, and monocyte-macrophage function, previously defective as measured by phagocytosis and plastic adherence, was restored. In a retrospective survey of 164 patients in whom bone marrow transplantation was performed in 14 European centers between 1969 and 1985, Fischer et al. (1986) found 11 cases of malignant osteopetrosis. In 6 of the 9, engraftment was successful. Bone lesions and hematopoietic abnormalities resolved, but neurosensory defects observed before bone marrow transplantation persisted in 2 of the patients. Four of the patients had shown normal mental development and little or no sensory impairment.

In addition to bone marrow transplantation for congenital osteopetrosis, high-dose calcitriol therapy was found by Key et al. (1984) to ameliorate osteopetrosis in 25% of patients. Key et al. (1995) stated that some patients, however, became refractory to calcitriol treatment.

The generation of superoxide by peripheral blood leukocytes is defective in patients with osteopetrosis (Beard et al., 1986). Patients with chronic granulomatous disease (CGD; 306400), in which there is a defect in superoxide generation, respond to therapy with recombinant human interferon gamma-1b (147570) with increased superoxide generation and fewer infections (Ezekowitz et al., 1988). Additionally, interferon gamma-1b increases marrow space in mice with osteopetrosis and microphthalmos (Rodriguiz et al., 1993). Key et al. (1992) treated 8 patients who had osteopetrosis with interferon gamma-1b for 6 months. During treatment, all the patients had increases in the production of superoxide by cultured leukocytes, decreases in the number of severe infections, and increases in bone resorption. Key et al. (1995) reported the results of treatment in 14 patients for at least 6 months; 11 of the patients were treated for 18 months. All patients had decreases in trabecular bone area and increases in bone marrow space. There was an increase in mean hemoglobin concentration from 7.5 to 10.5 g/dl. Superoxide generation by granulocyte-macrophage colonies increased. In 6 patients for whom pretreatment data were available, there was a 96% decrease in the frequency of infections requiring antibiotic therapy. The treatment was considered a reasonable therapeutic option for patients who were not candidates for BMT and an opportunity to stabilize the clinical condition of patients awaiting transplantation.

Gerritsen et al. (1994) reported outcomes of 69 patients who received allogeneic bone marrow grafts in the period between 1976 and 1994. In 4 patients who received bone marrow transplants without prior myeloablative conditioning, transient osteoblast function was demonstrated in one. Of the 65 patients who received myeloablative pretreatment, recipients of a genotypically HLA-identical BMT had an actuarial probability for 5-year survival with osteoclast function of 79%; recipients of a phenotypically HLA-identical bone marrow graft from a related or unrelated donor, or 1 HLA-mismatched graft from a related donor, had an actuarial probability for 5-year survival with osteoclast function of 38%; patients who received a graft from an HLA-haplotype mismatched related donor had a probability of 5-year survival of only 13%. Recovery of osteoclast function was associated with severe hypercalcemia in 24% of the patients with engraftment, especially those older than 2 years of age. Of the 15 patients who had visual impairment at the time that a successful BMT was performed, 2 had improvement after BMT (13%).

Population Genetics

By a systematic search for osteopetrosis in the county of Funen, Denmark, the prevalence of this category of bone disorder was found to be 5.5 per 100,000 persons (Bollerslev, 1987). Of the 33 patients, 32 had the mild, autosomal dominant form. Thirty-nine percent were asymptomatic. Two obligate carriers, who had the genotype but were not phenotypically affected, were found. The frequency of fractures was low. An unusually high frequency of recessive osteopetrosis has been observed in Costa Rica (Loria-Cortes et al., 1977).

Pathogenesis

Lajeunesse et al. (1996) demonstrated that human osteopetrotic osteoblast-like cells express a defective phenotype in primary cultures in vitro, and that BMT corrects osteoblast function. DNA analysis at polymorphic short tandem repeat loci from donor, recipient, and primary osteoblast-like cells before BMT and 2 years after BMT revealed that the osteoblast-like cells were still of recipient origin after BMT. Osteopetrotic osteoblast-like cells obtained before BMT showed normal production of 1,25(OH)2D3-induced alkaline phosphatase and abnormal osteocalcin production and failed to produce macrophage colony-stimulating factor (120420) in response to IL1-alpha and TNF-alpha. These parameters were all normalized in primary osteoblast-like cells prepared 2 years after BMT. X-linked clonality analysis at the human androgen receptor locus (313700) demonstrated that osteoblasts had a polyclonal and an oligo clonal derivation before and after BMT, respectively, indicating that a limited number of progenitor cells reconstituted this population. Because osteoblasts were still of recipient origin after BMT, this suggests that functional osteoclasts, due to the replacement of hematopoietic cells, provided a local microenvironment in vivo triggering the differentiation and/or recruitment of a limited number of functional osteoblasts.

Mapping

The phenotype in the malignant form of autosomal recessive osteopetrosis is similar to that of the murine mutation osteosclerosis (oc). Heaney et al. (1997, 1998) identified a novel gene that has homology to a family of 12-transmembrane domain transport proteins and mapped it to a region to which the oc mutation had previously been assigned. Given the similarity between the human and murine phenotypes, Heaney et al. (1997, 1998) used conservation of syntenic relationships between mouse and man to assess whether this novel gene should be considered a candidate for human osteopetrosis. Microsatellite markers in the region 11q12-q13 were found to be linked to osteopetrosis in 2 consanguineous Bedouin kindreds. Recombinant events were used to define the disease interval to a 5-cM region. They obtained a maximum lod score of 5.9 at D11S449 at theta = 0.0.

Molecular Genetics

Frattini et al. (2000) showed that TCIRG1 (604592), encoding the osteoclast-specific 116-kD subunit of the vacuolar proton pump, was mutated in 5 of 9 patients with infantile malignant osteopetrosis (see, e.g., 604592.0001-604592.0003). Kornak et al. (2000) reported 5 patients in whom different mutations were identified in at least 1 TCIRG1 allele (see, e.g., 604592.0004-604592.0005). An additional patient from a consanguineous family was not homozygous for markers flanking the locus, suggesting that a second locus may exist for infantile malignant osteopetrosis.

Janssens and Van Hul (2002) reviewed the process of bone remodeling and the genetic defects resulting in aberrant bone formation and resorption.

In a child from a consanguineous Turkish kindred who manifested osteopetrosis and distal RTA (see OPTB3, 259730), Borthwick et al. (2003) excluded defects in the CA2 gene and found instead penetrance of 2 separate recessive disorders, each affecting a different, tissue-specific subunit of the vacuolar proton pump H(+)-ATPase. The osteopetrosis was the result of a homozygous deletion in TCIRG1 (604592.0007), whereas the distal RTA was associated with a homozygous mutation in the ATP6V1B1 gene (192132.0005), which encodes the kidney-specific B1 subunit of H(+)-ATPase. Borthwick et al. (2003) concluded that coinheritance of 2 rare recessive disorders created a phenocopy of CA2 deficiency in this patient.

Animal Model

Walker (1975) showed that osteopetrosis could be induced in normal mice by intravenous injection of splenic cells into the lethally irradiated recipient from osteopetrotic sibs. This he interpreted to mean that (1) progenitors of osteoclasts are produced exclusively by the blood forming tissues; (2) ossification centers can be seeded with osteoclastic progenitors via the blood stream because of their homing capabilities; and (3) the osteoclast is the only cell type functionally incompetent in the osteopetrotic mouse.

Dominici et al. (2004) reported that hematopoietic cells and osteoblasts are derived from a common marrow progenitor after bone marrow transplantation in mice.