Osteoporosis-pseudoglioma syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Osteoporosis-pseudoglioma syndrome is a rare condition characterized by severe thinning of the bones (osteoporosis) and eye abnormalities that lead to vision loss. In people with this condition, osteoporosis is usually recognized in early childhood. It is caused by a shortage of minerals, such as calcium, in bones (decreased bone mineral density), which makes the bones brittle and prone to fracture. Affected individuals often have multiple bone fractures, including in the bones that form the spine (vertebrae). Multiple fractures can cause collapse of the affected vertebrae (compressed vertebrae), abnormal side-to-side curvature of the spine (scoliosis), short stature, and limb deformities. Decreased bone mineral density can also cause softening or thinning of the skull (craniotabes).

Most affected individuals have impaired vision at birth or by early infancy and are blind by young adulthood. Vision problems are usually caused by one of several eye conditions, grouped together as pseudoglioma, that affect the light-sensitive tissue at the back of the eye (the retina), although other eye conditions have been identified in affected individuals. Pseudogliomas are so named because, on examination, the conditions resemble an eye tumor known as a retinal glioma.

Rarely, people with osteoporosis-pseudoglioma syndrome have additional signs or symptoms such as mild intellectual disability, weak muscle tone (hypotonia), abnormally flexible joints, or seizures.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Osteoporosis-pseudoglioma syndrome is caused by mutations in the LRP5 gene. This gene provides instructions for making a protein that participates in a chemical signaling pathway that affects the way cells and tissues develop. In particular, the LRP5 protein helps regulate bone mineral density and plays a critical role in development of the retina.

LRP5 gene mutations that cause osteoporosis-pseudoglioma syndrome prevent cells from making any LRP5 protein or lead to a protein that cannot function. Loss of this protein's function disrupts the chemical signaling pathways that are needed for the formation of bone and for normal retinal development, leading to the bone and eye abnormalities characteristic of osteoporosis-pseudoglioma syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Osteoporosis-pseudoglioma syndrome is inherited in an autosomal recessive pattern, which means both copies of the LRP5 gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. However, some carriers may have decreased bone mineral density.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Osteoporosis-pseudoglioma syndrome is a rare disorder that occurs in approximately 1 in 2 million people.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Increased susceptibility to fractures · Very frequent (99-80%)

An abnormally increased tendency to fractures of bones caused by an abnormal reduction in bone strength that is generally associated with an increased risk of fracture.

Osteoporosis · Very frequent (99-80%)

Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility. According to the WHO criteria, osteoporosis is defined as a BMD that lies 2.5 standard deviations or more below the average value for young healthy adults (a T-score below -2.5 SD).

Abnormal vitreous humor morphology · Frequent (79-30%)

Any structural anomaly of the vitreous body.

Angle closure glaucoma · Frequent (79-30%)

A type of glaucomatous optic neuropathy in an eye that has evidence of angle closure (i.e. significant iridotrabecular contact).

Congenital blindness · Frequent (79-30%)

Blindness with onset at birth.

Corneal opacity · Frequent (79-30%)

A reduction of corneal clarity.

Crumpled long bones · Frequent (79-30%)

An crumpled radiographic appearance of the long bones, as if the long bone had been crushed together producing irregularities. This feature is the result of multiple fractures and repeated rounds of ineffective healing, as can be seen for instance in severe forms of osteogenesis imperfecta.

Floppy infant · Frequent (79-30%)

Floppiness/hypotonia is defined as reduced resistance to passive movement of joints. Physical examination of floppy/hypotonic infants shows head lag, lack of shoulder and elbow muscle contraction on traction response, inability to tighten the shoulder girdle muscles (or slipping through) when held under the axillae, scarf sign (when the arm is pulled to the opposite side, the arm wraps around the neck with the elbow crossing midline), hyperdorsiflexion of the feet, easy apposition of the thumb against the forearm, feet touching the cheek with ease and without discomfort, frog leg position, and inverted U sign on ventral suspension (head, arms, and legs hanging down without elbow or knee flexion and the trunk rounded in a dome shape).

Joint hypermobility · Frequent (79-30%)

The capability that a joint (or a group of joints) has to move, passively and/or actively, beyond normal limits along physiological axes.

Loss of ambulation · Frequent (79-30%)

Inability to walk in a person who previous had the ability to walk.

Low serum calcitriol · Frequent (79-30%)

The concentration of calcitriol in the blood circulation is below the lower limit of normal.

Metaphyseal widening · Frequent (79-30%)

Abnormal widening of the metaphyseal regions of long bones.

Osteopenia · Frequent (79-30%)

Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.

Retinal detachment · Frequent (79-30%)

Separation of the inner layers of the retina (neural retina) from the pigment epithelium.

Other findings in the same source

From: Orphanet

Additional reported features include Severely reduced visual acuity (Frequent (79-30%)); Waddling gait (Frequent (79-30%)); Abnormal lower limb bone morphology (Frequent (79-30%)); Exudative retinopathy (Frequent (79-30%)); Exudative vitreoretinopathy (Frequent (79-30%)); Congenital nystagmus (Occasional (29-5%)); Delayed gross motor development (Occasional (29-5%)); Delayed speech and language development (Occasional (29-5%)); Frontal bossing (Occasional (29-5%)); Global developmental delay (Occasional (29-5%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Osteoporosis-pseudoglioma syndrome is Orthopaedics, with a orthopaedic specialist as the relevant type of clinician. General physician / Family Medicine; paediatrician for children. Referral depends on symptoms.

Additional services that may be relevant, depending on the findings, include: Clinical Genetics.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• What explains the change in pain, movement or function?
• Which activities need adjustment while the diagnosis is being clarified?
• What are the roles of rehabilitation, observation and surgery in this situation?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Osteoporosis-pseudoglioma syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.