Osteopetrosis is a disorder of increased bone density due to defects in bone resorption. Several different forms are recognized and mutations in several genes have been described. Osteopetrosis, infantile malignant 1, 4, 5 (OPTB1; MIM 259700, OPTB4; MIM 611490, OPTB5; MIM 259720) is an autosomal recessive disorder caused by mutations in the TCIRG1, CLCN7, and OSTM1 genes. These genes code for the alpha subunit 3 of the vacuolar proton pump, the chloride channel 7 protein, and osteopetrosis associated transmembrane protein 1, respectively.

Malignant osteopetrosis patients have restricted cranial foramina, reduced bone marrow volume, fractures, deafness, osteomyelitis, short stature, genu valgum, large heads, and early death. CLCN7 mutations have also been described in both an intermediate autosomal recessive osteopetrosis and an autosomal dominant variant (OPTA2; MIM 166600). OPTA2 is a common form characterized by nontraumatic fractures, sclerosis of the spine with vertebral endplate thickening, sclerotic bone in the iliac wings, and sclerosis of the skull base. A second form of autosomal dominant osteopetrosis (OPTA1; MIM 607634) is caused by mutations in the LRP5 gene. OPTA1 is characterized by diffuse osteosclerosis with pronounced involvement of cranial bones. The cranial vault may be enlarged and a conductive hearing loss may be present. OPTA1 is not associated with an increased fracture rate.

Osteoclast-poor forms of autosomal recessive osteopetrosis, types 2 and 7 respectively, are caused by mutations in either the TNFSF11 (OPTB2; MIM 259710) or the TNFRSF11A (OPTB7; MIM 612301) genes. The TNFSF11 gene encodes the ligand, RANKL, and the TNFRSF11A encodes the receptor, RANK. A critical distinction between TNFSF11 and TNFRSF11A is that patients with TNFSF11 mutations do not respond to hematopoietic stem cell transplantation.

An intermediate form of autosomal recessive osteopetrosis 6 (OPTB6; MIM 611497) is caused by mutations in the PLEKHM1 gene, which codes for pleckstrin homology domain-containing protein, family M, member 1.

Autosomal recessive osteopetrosis 3 with renal tubular acidosis (OPTB3; MIM 259730) is caused by mutations in the gene coding for carbonic anhydrase II, CA2. CA2 catalyzes the formation of protons in the cytoplasm of osteoclasts.

In addition to renal tubular acidosis, OPTB3 is associated with intracerebral calcification, failure to thrive, developmental delay, and facial dysmorphism. These patients do not usually have fractures, but may be blind due to optic nerve compression.

Panel genes are also offered as individual sequencing and deletion/duplication tests, unless otherwise indicated.