El 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 ... El 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.
The 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 ... The 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.