Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.

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Loss of Functional Osteoprotegerin: More Than a Skeletal Problem.

J Clin Endocrinol Metab. 2016 Nov 3;:jc20162905

Authors: Grasemannn C, Unger N, Hövel M, Arweiler-Harbeck D, Herrmann R, Schündeln MM, Müller O, Schweiger B, Lausch E, Meissner T, Kiewert C, Hauffa BP, Shaw NJ

Abstract
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 structures (in 2 patients) resulted in early deafness. Patients were found to be growth hormone deficient (2) displayed elevated inflammatory markers (2), nephrocalcinosis (1) gross motor (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), visual impairment (2) and hearing impairment (1) were also present.
CONCLUSION: Diminished osteoprotegerin levels cause complex changes affecting multiple organ systems, including pituitary function, in children with JPD and may cause osteopenia in heterozygous family members. Diagnostic and therapeutic measures should aim to address the complex phenotype.

PMID: 27809640 [PubMed - as supplied by publisher]

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