2025 Aug 28. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2025.
ABSTRACT
CLINICAL CHARACTERISTICS: TCIRG1-related osteopetrosis is characterized by growth deficiency, pathologic fractures of dense but brittle bones, limping gait with bone pain, hypocalcemia that can result in seizures, and secondary hyperparathyroidism. Advanced bone sclerosis results in extramedullary hematopoiesis, bone marrow failure, ocular complications with potential for blindness (optic nerve compression/atrophy and primary retinopathy), dental manifestations (delay in tooth eruption and dental caries), and deafness in some individuals. Craniofacial features can include macrocephaly, exophthalmos, hypertelorism, and micrognathia. There is wide variability in clinical severity. Severe osteopetrosis with infantile onset is the most common phenotype, potentially resulting in death at a young age in the absence of successful treatment. Individuals with mild TCIRG1-related osteopetrosis may have normal growth without hematologic or neurologic abnormalities.
DIAGNOSIS/TESTING: The diagnosis of TCIRG1-related osteopetrosis is established in a proband with characteristic clinical, laboratory, and imaging findings and biallelic pathogenic variants in TCIRG1 identified by molecular genetic testing. Note: Heterozygous TCIRG1 pathogenic variants have been rarely reported in individuals with TCIRG1-related osteopetrosis.
MANAGEMENT: Targeted therapies: Hematopoietic stem cell therapy (HSCT) for those with hematologic failure with imminent vision loss, severe osteopetrosis with bone marrow failure, or severe osteopetrosis in children younger than age one year, ideally prior to age ten months. Interferon gamma-1b (IFN-γ1b) may be considered in infantile TCIRG1-related osteopetrosis, to serve as a bridge to HSCT.
Supportive care: Multidisciplinary management of complications includes treatment of fractures, skeletal deformities, and delayed healing per orthopedist; treatment of respiratory compromise per pulmonologist; calcium and vitamin D supplementation per endocrinologist; treatment of bone marrow failure and red blood cell transfusions per hematologist; dental treatment; management of hydrocephalus per neurosurgeon; treatment of hypocalcemia to prevent seizures; treatment of non-hypocalcemic seizures per neurologist; developmental and educational support; feeding therapy may become essential, requiring insertion of gastrostomy tube; optic nerve decompression and optic nerve sheath fenestration per neuro-ophthalmologist; surgical intervention for deafness per otolaryngologist; treatment of chronic/recurrent infections per infectious disease specialist; family and social work support.
Surveillance: Assess for frequency of fractures, skeletal deformities, and bone pain at each visit; assess for respiratory compromise and frequency of infections in those with small-volume thorax; serum calcium and phosphate every six to 12 months and every three months in those on calcitriol therapy; 25-hydroxyvitamin D and intact parathyroid hormone every six to 12 months; serum creatinine, calculation of glomerular filtration rate, and urinary calcium-to-creatinine ratio every three months in those on calcitriol therapy; renal ultrasound annually in those on calcitriol therapy; complete blood count with differential every six to 12 months; dental evaluation more frequently than every six months; neurologic exam with EEG if seizures are suspected every six months; head imaging per neurologist; assess developmental progress, educational needs, feeding, and growth at each visit; ophthalmology evaluation every six months until age 18 years, then annually through adulthood, with visual field exams in those who are old enough to participate and MRI of the optic nerves as clinically indicated; annual audiology evaluation in childhood and as needed in adults; assess family and social work needs at each visit.
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic sibs of a proband with TCIRG1-related osteopetrosis caused by missense variants; sibs found to be heterozygous for a TCIRG1 missense variant should be monitored for manifestations of osteopetrosis.
GENETIC COUNSELING: TCIRG1-related osteopetrosis is typically inherited in an autosomal recessive manner. Note: Heterozygous TCIRG1 pathogenic variants have been identified in affected individuals in one family with autosomal dominant osteopetrosis and one additional individual with a heterozygous de novo pathogenic variant.
If both parents are known to be heterozygous for a TCIRG1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of having TCIRG1-related osteopetrosis, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial TCIRG1 pathogenic variants. To date, manifestations of TCIRG1-related osteopetrosis have not been reported in heterozygous family members of a proband with TCIRG1-related osteopetrosis; however, it is theoretically possible that heterozygous sibs may be at risk for TCIRG1-related osteopetrosis. Once the TCIRG1 pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk family members and prenatal/preimplantation genetic testing are possible.