Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.

Introduction: Juvenile Pagets disease (JPD), an ultra-rare, debilitating bone disease stemming from unopposed RANKL action due to loss of functional osteoprotegerin (OPG) is caused by recessive mutations in TNFRSF11B. A genotype-phenotype correlation spanning from mild to very severe forms is described. Aim: To describe the complexity of the human phenotype of OPG deficiency in more detail and to investigate heterozygous mutation carriers for clinical signs of JPD. Patients and Methods: 3 children with JPD from families of Turkish, German and Pakistani descent and 19 family members (14 heterozygous) were investigated. Results: A new disease-causing 4 bp-duplication: c.[25-28dup];[25-28dup] in exon 1 was detected in the German patient and a homozygous microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in all affected children included bowing deformities and fractures, contractures, short stature and skull involvement. Complex malformation of the inner ear and vestibular str...