Osteopetrosis, Autosomal Dominant 3

A number sign (#) is used with this entry because of evidence that autosomal dominant osteopetrosis-3 (OPTA3) is caused by heterozygous mutation in the PLEKHM1 gene (611466) on chromosome 17q21.

An autosomal recessive form of osteopetrosis (OPTB6; 611497) is also caused by mutation in the PLEKHM1 gene.

Description

Autosomal dominant osteopetrosis-3 is characterized by phenotypic variability. Some patients have typical features of osteopetrosis, including fractures after minor trauma, early tooth loss, anemia, hepatosplenomegaly, and a generalized increase in bone mineral density, whereas other patients exhibit localized osteosclerosis and generalized osteopenia. OPTA3 represents a relatively malignant form of osteopetrosis in some patients who develop significant pancytopenia and hepatosplenomegaly (Bo et al., 2016).

For a discussion of genetic heterogeneity of autosomal dominant osteopetrosis, see OPTA1 (607634).

Clinical Features

Del Fattore et al. (2008) studied a 39-year-old Italian woman with an atypical osteopetrosis phenotype. At 3 years of age, she was diagnosed with rickets, and at age 28, with osteoporosis and vitamin D3 deficiency. X-rays at age 22 showed a modest increase in the thickness of the internal cortex of the frontal bone, and by age 31 there was a marked increase in thickness and hyperostosis in that bone segment. At age 36, x-rays showed radiolucent regions with inner discrete areas of increased bone density in the left femoral head and in the distal metaphysis of the right femur. At age 39, the patient experienced recurrent headaches, and skull x-rays showed a 5-mm radiolucent area in the frontoparietal bone that was osteolytic on CT scan but not metabolically active on scintigraphy. In addition, there was intense radiodensity of the skull base, osteophytes of the lumbar vertebral bodies, and osteolytic areas in the left femoral neck. Serum parathyroid hormone (PTH; 168450), osteocalcin (BGLAP; 112260), and tartrate-resistant acid phosphatase (TRACP) were elevated. The patient was diagnosed with osteopetrosis of the skull, but the authors noted that she also exhibited generalized osteopenia.

Bo et al. (2016) reported a 'middle-aged' Chinese man who presented with a history of frequent fractures, weakness, and fatigue. Examination revealed pale conjunctivae, pectus carinatum, 4 missing teeth, and hepatosplenomegaly, with reduced hemoglobin, white blood cell, and platelet levels, as well as significantly elevated PTH levels. X-rays showed generalized osteosclerosis of the cranial vault, cranial base, vertebrae, ribs, pelvis, and limbs. The calvarium was thickened and sclerotic, and the thoracic and lumbar spine exhibited intense radiodensity, with the typical 'sandwich vertebra' and 'bone-within-bone' appearance. There was increased density of the central pelvic bones, and a generalized increase in bone mineral density of the long bones. Radionuclide bone imaging revealed increased activity in the long bones and large joints as well as in the metacarpals bilaterally. Vertebral body bone biopsy exhibited the hallmarks of osteopetrosis, including unabsorbed calcified cartilage surrounded by bone and osteoclast aggregation, with obvious narrowing of the bone marrow cavity. Vision and hearing were normal, and there were no apparent neurologic deficits in the proband. His father reported excessive loss of teeth, but his mother, 2 sisters, and son and daughter were healthy, and radiologic and laboratory examinations of these relatives were unremarkable. Clinical follow-up in the proband over 4 years showed persistent significant anemia and hepatosplenomegaly despite treatment, indicating a relatively malignant form of osteopetrosis.

Molecular Genetics

In a 39-year-old Italian woman with osteopetrosis of the skull and generalized osteopenia, who was negative for mutation in the CLCN7 gene (602727), Del Fattore et al. (2008) analyzed the candidate gene PLEKHM1 and identified heterozygosity for a missense mutation (R714C; 611466.0002) that was not found in 48 Italian or 56 Belgian controls, nor in 30 additional osteopetrotic patients. Family members were unavailable for evaluation.

In a 'middle-aged' Chinese man with a relatively malignant form of osteopetrosis with significant anemia and hepatosplenomegaly, who was negative for mutation in the CLCN7 and TNFSF11 (602642) genes, Bo et al. (2016) identified heterozygosity for a de novo 2-bp deletion in the PLEKHM1 gene (611466.0003) which was not present in unaffected family members.