Osteoporosis-pseudoglioma syndrome (ORPHA:2788)
A rare bone disease characterized by congenital or infancy-onset blindness and juvenile-onset osteoporosis with spontaneous and low trauma fractures.
Epidemiology
The estimated prevalence is 1/2,000,000 but is higher in some founder populations (eg. Old Order Mennonites in Pennsylvania; 1.4/1000). Less than 100 cases have been reported.
Clinical description
Osteoporosis-pseudoglioma (OPPG) syndrome patients have reduced bone formation and poor bone quality. Fractures typically occur in both long bones and vertebrae, after age 2 until puberty. Some patients have eye pain severe enough to require enucleation. Additional clinical manifestations may include microphthalmos, cataracts, persistence of fetal fibrovascular system and absent retinal development, vitreoretinal dysplasia, pseudogliomatous retinal detachments and phthisis bulbi, short stature, microcephaly, ligamental laxity, and hypotonia. Cognitive difficulty and behavioral issues have been reported but most patients have neither.
Etiology
The disease is caused by biallelic mutations in the low-density lipoprotein receptor related protein 5 gene (LRP5). The severity of the osteoporosis varies by mutation but most patients have complete blindness by early infancy. With less severe mutations, some vision may persist into childhood. Heterozygotes may have reduced bone density or osteoporosis but have normal vision.
Diagnostic methods
Diagnosis is suspected on clinical presentation (typically congenital blindness and white pupils) and confirmed by genetic testing. Fragility fractures are generally not diagnosed < age 2 and normative bone density data are not available for children < age 3, so fragility fractures and osteoporosis by bone density are not required for diagnosis.
Differential diagnosis
Osteogenesis imperfecta is the primary differential diagnosis for osteoporosis. Familial exudative vitreoretinopathy and Norrie disease are the differential diagnoses for congenital blindness and pseudoglioma.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic LRP5 variant has been identified in a family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation). Heterozygote carriers have normal vision but may have low bone mass or osteoporosis.
Management and treatment
Examination by an ophthalmologist is recommended as soon as possible. In rare patients who have retained light perception at birth, laser therapy (for retinal detachment) may be successful in maintaining some vision, at least temporarily. For osteoporosis, intravenous (pamidronate) and oral (alendronate) bisphosphonates have been used successfully to increase bone density and appear to reduce fracture risk. However, due to the rarity of OPPG, no placebo-controlled trial has been reported. Maintenance of vitamin D sufficiency is important. Age of initiation and duration of treatment need to be individualized. Treatment can be delayed until after age 3 since fractures typically do not occur prior to age 2. Treatment can generally be stopped at puberty when fracture risk decreases. In patients treated from childhood until puberty, it is possible that treatment may need to be restarted when bone aging starts (after menopause in women and after 50 in men). Anabolic bone agents are contraindicated in children, but teriparatide has been reported to be successful in an adult and an adolescent with OPPG. As in other forms of juvenile osteoporosis, leg bowing may occur in childhood and may require surgical management.
Prognosis
Besides blindness and osteoporosis there are no other chronic medical problems that have definitively been associated with OPPG. There is no known impact on life expectancy. With appropriate osteoporosis treatment, ambulation is maintained in most patients. Chronic pain due to compression fractures of the spine can occur. Morbidity in most patients is due to blindness, which is complete (no light perception) in most. There have been no quality of life studies reported in OPPG.

                            Last update: 
                            July 2023


                            - Expert reviewer(s): 
                            Dr Elizabeth STREETEN