Background: 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.
Objective and hypotheses: 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.
Method: About three children with JPD from families of Turkish, German and Pakistani descent and 18 family members (13 heterozygous) were investigated.
Results: A new disease-causing 4 bp-duplication: c.[2528dup];[2528dup] in exon one was detected in the German patient and a homozygous microdeletion including TNFRFSF11B in the Pakistani patient. Skeletal abnormalities in the affected children include bowing deformities and fractures (three patients), contractures (3), short stature (3) and skull involvement (3). Complex malformation of the inner ear (3) and vestibular structures (2) resulted in early deafness. Patients were found to be growth hormone deficient (2) displayed elevated inflammatory markers (2), nephrocalcinosis (1) motoric (3) and mental (1) retardation. No retinal changes were observed in any of the patients. Heterozygous family members displayed low osteoprotegerin levels (12), elevated bone turnover markers (7) and osteopenia (6). Short stature (1), vision impairment (2) and hearing impairment (1) were also present.
Conclusion: Diminished osteoprotegerin levels cause complex changes affecting multiple organ systems in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.
10 - 12 Sep 2016
European Society for Paediatric Endocrinology