Polycystic Lipomembranous Osteodysplasia with Sclerosing Leukoencephalopathy.

Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) is characterized by fractures (resulting from radiologically demonstrable polycystic osseous lesions), frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Death usually occurs before age 50 years. The clinical course of PLOSL can be divided into four stages: (1) The latent stage is characterized by normal early development. (2) The osseous stage (3rd decade of life) is characterized by pain and tenderness, mostly in ankles and feet, usually following strain or injury. Fractures are typically diagnosed several years later, most commonly in the bones of the extremities. (3) In the early neurologic stage (4th decade of life), a change of personality begins to develop insidiously. Affected individuals show a frontal lobe syndrome (loss of judgment, euphoria, loss of social inhibitions, disturbance of concentration, and lack of insight, libido, and motor persistence) leading to serious social issues. (4) The late neurologic stage is characterized by progressive dementia and loss of mobility. The diagnosis of PLOSL can be established in a proband with radiologically demonstrable polycystic osseous lesions, frontal lobe syndrome, and progressive presenile dementia beginning in the fourth decade. Identification of biallelic pathogenic variants in TYROBP or TREM2 confirms the diagnosis since radiographic and clinical features may be inconclusive. Treatment of manifestations: Treatment is symptomatic. Standard orthopedic management of fractures; pain management; supportive orthopedic devices may be helpful; symptomatic medication may be applied for behavioral symptoms; psychological support and early education of family members and caregivers; anti-seizure medication can be used to prevent epileptic seizures and secondary worsening of the condition. Surveillance: Clinical evaluation for evidence of fractures; neurologic and neuropsychiatric examination with frequency as needed; assess family/caregiver needs at each visit. PLOSL is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a TREM2 or TYROBP pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygous sibs of a proband with PLOSL are not at risk of developing PLOSL. However, individuals heterozygous for a TYROBP pathogenic variant may have cyst-like bone lesions without presenile dementia, and population studies of individuals heterozygous for the TYROBP 5.2-kb deletion show an increased risk for developing Alzheimer disease. Once the PLOSL-related pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk family members, predictive testing for at-risk sibs, and prenatal/preimplantation genetic testing are possible.