Osteopetrosis, Autosomal Recessive 5
A number sign (#) is used with this entry because of evidence that autosomal recessive osteopetrosis-5 (OPTB5) is caused by homozygous mutation in the gene encoding osteopetrosis-associated transmembrane protein-1 (OSTM1; 607649) on chromosome 6q21.
For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive osteopetrosis, see OPTB1 (259700).
DescriptionAutosomal recessive osteopetrosis-5 is a form of infantile malignant osteopetrosis, characterized by defective osteoclast function resulting in decreased bone resorption and generalized osteosclerosis. Defective resorption causes development of densely sclerotic fragile bones and progressive obliteration of the marrow spaces and cranial foramina. Marrow obliteration is associated with extramedullary hematopoiesis and hepatosplenomegaly, and results in anemia and thrombocytopenia, whereas nerve entrapment accounts for progressive blindness and hearing loss. Other major manifestations include failure to thrive, pathologic fractures, and increased infection rate. Most affected children succumb to severe bone marrow failure and overwhelming infection in the first few years of life (Quarello et al., 2004).
Clinical FeaturesEl Khazen et al. (1986) reported severe osteopetrosis with in utero fractures in 2 successive offspring, a male and a female, born of first-cousin Moroccan parents. They suggested that this was a distinct entity because osteoclasts were markedly reduced (they are usually increased in severe recessive osteopetrosis) and clinical expression occurred very early. Hydrocephaly and skeletal hyperdensity were detected at 18 weeks of gestation and fractures at 24 weeks. The female was stillborn, and the pregnancy with the male was terminated at 25 weeks. Severe histologic changes were described in the brain.
Abinun et al. (1999) reported 5 patients with infantile osteopetrosis who had radiographically demonstrated generalized osteosclerosis, anemia, hepatosplenomegaly, and normal renal tubular function. Bone marrow examination revealed the typical overproliferation of osteoclasts in 3 patients, but virtually no osteoclasts were present in 2 patients (their patients 4 and 5). In addition, patient 4 had severe visual impairment with optic atrophy, abnormal retinal pigmentary changes, absent visual evoked responses, hypertonicity, microcephaly, and marked cerebral atrophy. Abinun et al. (1999) noted that bone marrow transplantation (BMT) was not attempted in this patient because BMT does not influence the progressive course of the neurodegenerative disorder in severe osteopetrosis.
Quarello et al. (2004) provided a phenotypic description of the Italian male infant previously studied by Chalhoub et al. (2003) (see later), who presented at 9 days of age with severe osteopetrosis including marked hepatosplenomegaly, cytopenia, and progressive liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation, and the bone marrow was hypocellular. The infant died at 31 days of age due to multiorgan failure; postmortem bone histopathology showed absence of resorptive activity, and osteoclasts were slightly decreased in number and elongated, with pericapillary localization.
Clinical Variability
Mahmoud Adel et al. (2013) reported a 9-month-old Arab boy, born to first-cousin parents, who presented with the triad of osteopetrosis, craniosynostosis, and Chiari malformation type I. Irritability was observed from the second week of life, and head CT at age 3 months showed brain atrophy. Although the proband had initially been able to fix and follow, he exhibited roving eye movements at 3 months of age, and visual evoked potentials at 8 months were consistent with bilateral optic atrophy. Clinical evaluation at 9 months of age showed microcephaly and closed anterior fontanel as well as ridging of coronal and sagittal sutures. He had bilateral proptosis with dilated pupils and sluggish reaction to light; other cranial nerves appeared to be intact. He had mild hypertonia in all limbs, with axial hypotonia. Brain CT showed dilated ventricles with thick skull bones and fusion of coronal and sagittal sutures, and skeletal survey showed generalized increased bone density and sclerosed medullary spaces. MRI after placement of a ventriculoperitoneal shunt showed decompression of ventricles and presence of a Chiari I malformation. Postoperatively there were signs of left lower motor neuron facial palsy, and repeat CT of petrous bones showed osteopetrosis with 'slim' mastoid portions of the facial nerve canal on both sides.
Molecular GeneticsThe spontaneous mouse 'grey-lethal' (gl) mutation is responsible for a coat color defect and for the development of the most severe autosomal recessive form of osteopetrosis. Using a positional cloning approach, Chalhoub et al. (2003) cloned the mouse gl gene and its human homolog, OSTM1 (607649). They analyzed the OSTM1 gene in 19 patients with autosomal recessive osteopetrosis who were negative for mutations in the TCIRG1 (604592) and CLCN7 (602727) genes, and identified a splice site mutation (607649.0001) in a patient of Italian origin. The asymptomatic parents were heterozygous for the mutation, which was not found in 100 control chromosomes. Studies in mouse demonstrated that gl protein function is absolutely required for osteoclast and melanocyte maturation and function.
Ramirez et al. (2004) reported a 3-month-old girl, born of second-cousin Kuwaiti parents, who had severe osteopetrosis with hepatosplenomegaly, thrombocytopenia, and neurologic symptoms. She was negative for mutations in TCIRG1 and CLCN7. Based on haplotype homozygosity at chromosome 6q21 in the patient, the authors sequenced the OSTM1 gene and identified homozygosity for a 2-bp deletion (607649.0002). The parents were heterozygous for the mutation, which was not found in 100 German control chromosomes. The patient had an older brother with osteopetrosis who had died at age 6 months after unsuccessful BMT.
Pangrazio et al. (2006) analyzed the OSTM1 gene in 160 patients with a clinical diagnosis of severe osteopetrosis who were negative for mutations in the TCIRG1 and CLCN7 genes. They identified homozygosity for the previously reported 2-bp deletion (607649.0002) in a Kuwaiti boy (patient 4 in Abinun et al., 1999) and an unrelated Kuwaiti girl, and found homozygosity for a nonsense mutation (C12X; 607649.0003) in a Lebanese boy.
In a 9-month-old Arab boy with osteopetrosis, craniosynostosis, and Chiari malformation type I, who was negative for mutation in the CLCN7 and TCIRG1 genes, Mahmoud Adel et al. (2013) analyzed the OSTM1 gene and identified homozygosity for 2 mutations: a V122D missense mutation, and a c.108C-T transition resulting in a synonymous mutation (G36G). The proband's first-cousin parents were each heterozygous for both mutations. The authors noted that because V122 is not a highly conserved residue, V122D might represent a neutral variant; they also suggested that the c.108C-T variant might create a new donor splice site (GT), but no functional analysis was reported.
Animal ModelBrown and Dent (1971) reviewed theories of pathogenesis and described probable models in the mouse and rabbit. Similarities to the grey-lethal mutation in the mouse, which seemed to be a thyrocalcitonin excess disease, stimulated search for abnormality of this hormone in osteopetrosis and other osteosclerotic conditions. However, Walker (1973) presented evidence that the osteopetrosis of the grey-lethal and microphthalmic mice is not primarily related to calcitonin or parathyroid hormone overproduction. Temporary parabiosis with normal littermates resulted in permanent cure. He suggested that the procedure had resulted in recruitment of progenitors of competent osteolytic cells from the blood of the normal mouse.