Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, commonly known as PLOSL, is a progressive disorder that affects the bones and brain. "Polycystic lipomembranous osteodysplasia" refers to cyst-like bone changes that can be seen on x-rays. "Sclerosing leukoencephalopathy" describes specific changes in the brain that are found in people with this disorder.

The bone abnormalities associated with PLOSL usually become apparent in a person's twenties. In most affected individuals, pain and tenderness in the ankles and feet are the first symptoms of the disease. Several years later, broken bones (fractures) begin to occur frequently, particularly in the bones of the ankles, feet, wrists, and hands. Bone pain and fractures are caused by thinning of the bones (osteoporosis) and cysts in the bones. These abnormalities weaken bones and make them more likely to break.

The brain abnormalities characteristic of PLOSL typically appear in a person's thirties. Personality changes are among the first noticeable problems, followed by a loss of judgment, feelings of intense happiness (euphoria), a loss of inhibition, and poor concentration. These neurologic changes cause significant problems in an affected person's social and family life. As the disease progresses, it causes a severe decline in thinking and reasoning abilities (dementia). Affected people ultimately become unable to walk, speak, or care for themselves. People with this disease usually live only into their thirties or forties.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Variants (also called mutations) in the TREM2 gene or the TYROBP gene can cause PLOSL. The proteins produced from these two genes work together to activate certain kinds of cells. These proteins appear to be particularly important in osteoclasts, which are specialized cells that break down and remove (resorb) bone tissue that is no longer needed. Osteoclasts are involved in bone remodeling, which is a normal process that replaces old bone tissue with new bone. The TREM2 and TYROBP proteins are also critical for the normal function of microglia, which are a type of immune cell in the brain and spinal cord (central nervous system). Although these proteins play essential roles in osteoclasts and microglia, their exact function in these cells is unclear.

Variants in the TREM2 or TYROBP gene disrupt normal bone remodeling and lead to progressive brain abnormalities in people with PLOSL. Researchers believe that the bone changes seen in people with this disorder are related to malfunctioning osteoclasts, which are less able to resorb bone tissue during bone remodeling. In the central nervous system, TREM2 or TYROBP gene variants cause widespread abnormalities of microglia. Researchers are working to determine how these abnormalities lead to the neurological problems associated with PLOSL.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell must have a variant to cause the disorder. The parents of an individual with an autosomal recessive condition each carry one copy of the altered gene, but they typically do not show signs and symptoms of the condition.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

PLOSL is a very rare condition. It was first reported in the Finnish population, where it has an estimated prevalence of 1 to 2 per million people. This condition has also been diagnosed in more than 100 people in the Japanese population. Although affected individuals have been reported worldwide, PLOSL appears to be less common in other countries.

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.

Abnormal adipose tissue morphology · Very frequent (99-80%)

An abnormality of adipose tissue, which is loose connective tissue composed of adipocytes.

Abnormality of epiphysis morphology · Very frequent (99-80%)

An anomaly of epiphysis, which is the expanded articular end of a long bone that developes from a secondary ossification center, and which during the period of growth is either entirely cartilaginous or is separated from the shaft by a cartilaginous disk.

Arthralgia · Very frequent (99-80%)

Joint pain.

Atypical behavior · Very frequent (99-80%)

Atypical behavior is an abnormality in a person's actions that can be controlled or modulated by the will of the individual. While abnormal behaviors can be difficult to control, they are distinct from other abnormal actions that cannot be affected by the individual's will.

Bone cyst · Very frequent (99-80%)

A fluid filled cavity that develops with a bone.

Bone pain · Very frequent (99-80%)

An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.

Cerebral cortical atrophy · Very frequent (99-80%)

Atrophy of the cortex of the cerebrum.

Developmental regression · Very frequent (99-80%)

Loss of developmental skills, as manifested by loss of developmental milestones.

Other findings in the same source

From: Orphanet

Additional reported features include Disinhibition (Very frequent (99-80%)); Irritability (Very frequent (99-80%)); Limitation of joint mobility (Very frequent (99-80%)); Memory impairment (Very frequent (99-80%)); Personality changes (Very frequent (99-80%)); Reduced bone mineral density (Very frequent (99-80%)); Skeletal dysplasia (Very frequent (99-80%)); Ventriculomegaly (Very frequent (99-80%)); Frontal lobe dementia (Very frequent (99-80%)); Abnormality of movement (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 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 Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. 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.