Clinical characteristics: The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease).

1. ARO. Onset is at birth. Findings may include: fractures; reduced growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years.

2. IAO. Onset is in childhood. Findings may include: fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal.

3. ADOII. Onset is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.

Diagnosis/testing: The diagnosis of a CLCN7-related osteopetrosis is established in a proband with suggestive findings and biallelic pathogenic variants or a heterozygous pathogenic variant in CLCN7 identified by molecular genetic testing.

Management: Treatment of manifestations:

1. ARO. Calcium supplementation for hypocalcemic convulsions; management of calcium homeostasis per individual needs; erythrocyte or platelet transfusions as needed; antibiotics for leukocytopenia; immunoglobulins for hypogammaglobulinemia. Newly diagnosed individuals should be transferred as soon as possible to a pediatric center experienced in allogeneic stem cell transplantation in this disease. The collaboration of pediatricians, pediatric neurologists, ophthalmologists, and psychologists is required to determine best treatment of neurologic and ophthalmic issues, which may include surgical decompression of the optic nerve and hearing aids. Treatment of fractures by an experienced orthopedist and dental care with attention to tooth eruption, ankylosis, abscesses, cysts, and fistulas.

2. ADOII. Orthopedic treatment for fractures and arthritis with attention to potential post-surgical complications (delayed union or non-union of fractures, infection); fractures near joints may require total joint arthroplasty. Medical treatment for arthritis with anti-inflammatory agents; transfusions for anemia and thrombocytopenia; surgical optic nerve decompression, hearing aids, and regular dental care and good oral hygiene.

Prevention of primary manifestations: In ARO, hematopoietic stem cell transplantation (HSCT) can be curative; however, cranial nerve dysfunction is usually irreversible, and progressive neurologic sequelae occur in children with the neuronopathic form even after successful HSCT.

Surveillance: Complete blood count, ophthalmologic examination, and audiologic evaluation at least once a year; dental evaluation every 6-12 months or as directed. For ARO, follow up as directed by the transplantation center following HSCT.

Agents/circumstances to avoid: In ADOII, activities with high fracture risk. Orthopedic surgery should only be performed when absolutely necessary.

Genetic counseling: CLCN7-related osteopetrosis is inherited in an autosomal recessive or autosomal dominant manner: ARO is inherited in an autosomal recessive manner; about 40% of IAO is inherited in an autosomal recessive manner and about 60% in an autosomal dominant manner; and ADOII is inherited in an autosomal dominant manner.

1. Autosomal recessive inheritance. If both parents are known to be heterozygous for a CLCN7 pathogenic variant associated with autosomal recessive osteopetrosis, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial CLCN7 pathogenic variants. Carrier testing for at-risk relatives requires prior identification of the CLCN7 pathogenic variants in the family.

2. Autosomal dominant inheritance. Most individuals diagnosed with autosomal dominant CLCN7-related osteopetrosis have an affected parent. Each child of an individual with autosomal dominant osteopetrosis has a 50% chance of inheriting the pathogenic variant.

Once the CLCN7 pathogenic variant(s) have been identified in an affected family member, prenatal testing and preimplantation genetic testing for CLCN7-related osteopetrosis are possible.